22. The compound according to claim 1, wherein R5, R6, and
R7 are each H.

23. The compound according to claim 1, wherein R8 is aryl,
C3-10 cycloalkyl, or heteroaryl each optionally substituted with
substituents selected independently from the group consisting of
C1-6 alkoxy, C1-6 alkyl, cyano, halogen, C1-6 haloalkoxy,
and C1-6 haloalkyl.

24. The compound according to claim 1, wherein R8 is phenyl,
cyclopropyl, or isoxazolyl each optionally substituted with substituents
selected independently from the group consisting of C1-6 alkoxy,
C1-6 alkyl, cyano, halogen, C1-6 haloalkoxy, and C1-6
haloalkyl.

[0002] The present invention also relates to the methods for the treatment
of 5-HT2A serotonin receptor associated disorders in combination
with other pharmaceutical agents administered separately or together.

BACKGROUND OF THE INVENTION

G Protein Coupled Receptors

[0003] G Protein coupled receptors share a common structural motif. All
these receptors have seven sequences of between 22 to 24 hydrophobic
amino acids that form seven alpha helices, each of which spans the
membrane. The transmembrane helices are joined by strands of amino acids
having a larger loop between the fourth and fifth transmembrane helix on
the extracellular side of the membrane. Another larger loop, composed
primarily of hydrophilic amino acids, joins transmembrane helices five
and six on the intracellular side of the membrane. The carboxy terminus
of the receptor lies intracellularly with the amino terminus in the
extracellular space. It is thought that the loop joining helices five and
six, as well as, the carboxy terminus, interact with the G protein.
Currently, Gq, Gs, Gi and Go are G proteins that have been identified.

[0004] Under physiological conditions, G protein coupled receptors exist
in the cell membrane in equilibrium between two different states or
conformations: an "inactive" state and an "active" state. A receptor in
an inactive state is unable to link to the intracellular transduction
pathway to produce a biological response. Changing the receptor
conformation to the active state allows linkage the transduction pathway
and produces a biological response.

[0005] A receptor may be stabilized in an active state by an endogenous
ligand or an exogenous agonist ligand. Recent discoveries such as,
including but not exclusively limited to, modifications to the amino acid
sequence of the receptor provide means other than ligands to stabilize
the active state conformation. These means effectively stabilize the
receptor in an active state by simulating the effect of a ligand binding
to the receptor. Stabilization by such ligand-independent means is termed
"constitutive receptor activation."

[0006] Serotonin Receptors

[0007] Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an
important class of G protein coupled receptors. Serotonin is thought to
play a role in processes related to learning and memory, sleep,
thermoregulation, mood, motor activity, pain, sexual and aggressive
behaviors, appetite, neurodegenerative regulation, and biological
rhythms. Not surprisingly, serotonin is linked to pathophysiological
conditions such as anxiety, depression, obsessive compulsive disorders,
schizophrenia, suicide, autism, migraine, emesis, alcoholism, and
neurodegenerative disorders. With respect to anti-psychotic treatment
approaches focused on the serotonin receptors, these types of
therapeutics can generally be divided into two classes, the "typical" and
the "atypical." Both have anti-psychotic effects, but the typicals also
include concomitant motor-related side effects (extra pyramidal
syndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc).
Such side effects are thought to be associated with the compounds
interacting with other receptors, such as the human dopamine D2
receptor in the nigro-striatal pathway. Therefore, an atypical treatment
is preferred. Haloperidol is considered a typical anti-psychotic, and
clozapine is considered an atypical anti-psychotic.

[0008] Serotonin receptors are divided into seven subfamilies, referred to
as 5-HT1 through 5-HT7, inclusive. These subfamilies are
further divided into subtypes. For example, the 5-HT2 subfamily is
divided into three receptor subtypes: 5-HT2A, 5-HT2B, and
5-HT2C. The human 5-HT2C receptor was first isolated and cloned
in 1987, and the human 5-HT2A receptor was first isolated and cloned
in 1990. These two receptors are thought to be the site of action of
hallucinogenic drugs. Additionally, antagonists to the 5-HT2A and
5-HT2C receptors are believed to be useful in treating depression,
anxiety, psychosis, and eating disorders.

[0009] U.S. Pat. No. 4,985,352 describes the isolation, characterization,
and expression of a functional cDNA clone encoding the entire human
5-HT1C receptor (now known as the 5-HT2C receptor). U.S. Pat.
Nos. 5,661,024 and 6,541,209 describe the isolation, characterization,
and expression of a functional cDNA clone encoding the entire human
5-HT2A receptor.

[0010] Mutations of the endogenous forms of the rat 5-HT2A and rat
5-HT2C receptors have been reported to lead to constitutive
activation of these receptors (5-HT2A: Casey, C. et al. (1996)
Society for Neuroscience Abstracts, 22:699.10, hereinafter "Casey";
5-HT2C: Herrick-Davis, K., and Teitler, M. (1996) Society for
Neuroscience Abstracts, 22:699.18, hereinafter "Herrick-Davis 1"; and
Herrick-Davis, K. et al. (1997) J. Neurochemistry 69(3): 1138,
hereinafter "Herrick-Davis-2"). Casey describes a mutation of the
cysteine residue at position 322 of the rat 5-HT2A receptor to
lysine (C322K), glutamine (C322Q), and arginine (C322R) which reportedly
led to constitutive activation. Herrick-Davis 1 and Herrick-Davis 2
describe mutations of the serine residue at position 312 of the rat
5-HT2C receptor to phenylalanine (S312F) and lysine (S312K), which
reportedly led to constitutive activation.

SUMMARY OF THE INVENTION

[0011] One aspect of the present invention pertains to certain compounds
as shown in Formula (Ia):

##STR00002##

[0012] or a pharmaceutically acceptable salt, hydrate or solvate thereof;

[0027] One aspect of the present invention pertains to pharmaceutical
compositions comprising a compound of the present invention and a
pharmaceutically acceptable carrier.

[0028] One aspect of the present invention pertains to methods for
modulating the activity of a 5-HT2A serotonin receptor by contacting
the receptor with a compound according to any of the embodiments
described herein or a pharmaceutical composition thereof.

[0029] One aspect of the present invention pertains to methods for
treating a 5-HT2A associated disorder in an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound according to any of the embodiments
described herein or a pharmaceutical composition thereof.

[0030] One aspect of the present invention pertains to methods for
treating a 5-HT2A serotonin receptor associated disorder in an
individual comprising administering to the individual in need thereof a
therapeutically effective amount of a compound according to any of the
embodiments described herein wherein R4a is metabolically-labile
group.

[0031] One aspect of the present invention pertains to methods for
treating a 5-HT2A serotonin receptor associated disorder in an
individual comprising administering to the individual in need thereof a
therapeutically effective amount of a prodrug whereby the prodrug
undergoes a conversion into a compound according to any of the
embodiments described herein wherein R4a is H and the conversion
takes place within the body of the individual.

[0032] One aspect of the present invention pertains to processes for
preparing a composition comprising admixing a compound according to any
of the embodiments described herein and a pharmaceutically acceptable
carrier.

[0033] One aspect of the present invention pertains to the use of a
compound of the present invention for the production of a medicament for
use in the treatment of a 5-HT2A associated disorder.

[0034] One aspect of the present invention pertains to compounds according
to any of the embodiments described herein for use in a method of
treatment of the human or animal body by therapy.

[0035] One aspect of the present invention pertains to compounds according
to any of the embodiments described herein for use in a method for the
treatment of a 5-HT2A associated disorder, as described herein, in
the human or animal body by therapy.

[0036] These and other aspects of the invention disclosed herein will be
set forth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 shows the general synthetic scheme for the preparation of
intermediate compounds of the present invention. FIG. 1 shows a general
coupling method between a pyrazole boronic acid and an aryl triflate, it
is understood that similar coupling methods known in the art can also be
used, and a halide, such as, I, Br or Cl, can be used in place of the
triflate.

[0038]FIG. 2 shows the general synthetic scheme for the preparation of
intermediate compounds of the present invention wherein "V" is oxygen.
FIG. 2 shows a general coupling method between a pyrazole boronic acid
and a phenyl halide using coupling methods known in the art, such as a
Suzuki coupling, and the like. FIG. 2 further shows the use of orthogonal
protecting groups for the oxygen (V═O) and the nitrogen. After the
coupling reaction the phenol protecting group is removed and a variety of
--W-Q groups can be introduced. Subsequently, the alkyl amide protecting
group can be hydrolyzed to provide the amine intermediate of the present
invention.

[0039]FIG. 3 shows the general synthetic scheme for the preparation of
intermediate compounds of the present invention. FIG. 3 illustrates
general methods for introducing a variety of halogens to compounds of the
invention. It is understood that these halogenation reactions can also be
conducted later in the synthesis, for example as the last step.

[0040]FIG. 4 shows the general synthetic scheme for the preparation of
intermediate compounds of the present invention. FIG. 4 shows the general
reactions, such as, alkylation and Mitsunobu-like reactions, for
introducing the --W-Q group.

[0041]FIG. 5 shows the general synthetic scheme for the preparation of
compounds of the present invention. FIG. 5 shows the general coupling
reactions of the amino-intermediate with carboxylic acids, acyl halides,
and the like.

[0042]FIG. 6 shows the general synthetic scheme for the preparation of
intermediates and compounds of the present invention. FIG. 6 illustrates
the general methods for preparing pyrazoles of the present invention
using substituted and unsubstituted hydrazines.

[0043]FIG. 7 shows the general synthetic scheme for the preparation of
compounds of the invention wherein the --W-Q group is introduced in the
last step(s). FIG. 7 shows the general reactions, such as, alkylation and
Mitsunobu-like reactions, for introducing the --W-Q group.

[0044] FIG. 8 shows the general synthetic scheme for the preparation of
compounds of the invention wherein V is NH in Formula (Ia) and the --W-Q
group is introduced in the last step(s). FIG. 8 shows the general
reactions, such as, alkylation reactions, for introducing the --W-Q group
wherein V is NH.

DEFINITIONS

[0045] The scientific literature that has evolved around receptors has
adopted a number of terms to refer to ligands having various effects on
receptors. For clarity and consistency, the following definitions will be
used throughout this patent document.

[0046] The term "agonists" shall mean moieties that interact and activate
the receptor, such as the 5-HT2A receptor, and initiates a
physiological or pharmacological response characteristic of that
receptor. For example, when moieties activate the intracellular response
upon binding to the receptor, or enhance GTP binding to membranes.

[0047] The term "antagonist" is intended to mean moieties that
competitively bind to the receptor at the same site as agonists (for
example, the endogenous ligand), but which do not activate the
intracellular response initiated by the active form of the receptor, and
can thereby inhibit the intracellular responses by agonists or partial
agonists. Antagonists do not diminish the baseline intracellular response
in the absence of an agonist or partial agonist.

[0048] The term "contact or contacting" is intended to mean bringing the
indicated moieties together, whether in an in vitro system or an in vivo
system. Thus, "contacting" a H3 receptor with a compound of the invention
includes the administration of a compound of the present invention to an
individual, preferably a human, having a H3 receptor, as well as, for
example, introducing a compound of the invention into a sample containing
a cellular or more purified preparation containing a H3 receptor.

[0049] The term "in need of treatment" is intended to mean a judgment made
by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the
case of humans; veterinarian in the case of animals, including non-human
mammals) that an individual or animal requires or will benefit from
treatment. This judgment is made based on a variety of factors that are
in the realm of a caregiver's expertise, but that includes the knowledge
that the individual or animal is ill, or will become ill, as the result
of a disease, condition or disorder that is treatable by the compounds of
the invention. Accordingly, the compounds of the invention can be used in
a protective or preventive manner; or compounds of the invention can be
used to alleviate, inhibit or ameliorate the disease, condition or
disorder.

[0050] The term "individual" is intended to mean any animal, including
mammals, preferably mice, rats, other rodents, rabbits, dogs, cats,
swine, cattle, sheep, horses, or primates, and most preferably humans.

[0051] The term "inverse agonists" is intended to mean moieties that bind
the endogenous form of the receptor or to the constitutively activated
form of the receptor, and which inhibit the baseline intracellular
response initiated by the active form of the receptor below the normal
base level of activity which is observed in the absence of agonists or
partial agonists, or decrease GTP binding to membranes. Preferably, the
baseline intracellular response is inhibited in the presence of the
inverse agonist by at least 30%, more preferably by at least 50%, and
most preferably by at least 75%, as compared with the baseline response
in the absence of the inverse agonist.

[0052] The term "isolated" refers to material that is removed from its
original environment (e.g., the natural environment if it is naturally
occurring). For example, a metabolite that is formed from a parent
compound present in a natural system (e.g. individual) is not isolated,
but the same metabolite, separated from some or all of the coexisting
materials in the natural system, is considered isolated. In addition, the
metabolite that is prepared by synthetic means is also considered
isolated.

[0053] The term "modulate or modulating" is intended to mean an increase
or decrease in the amount, quality, response or effect of a particular
activity, function or molecule.

[0054] The term "metabolically-labile group" as used herein refers to any
group that, following administration of a compound containing the group
to an individual, is converted in vivo to a compound of Formula (Ia)
wherein R4a is H. The conversion of the "metabolically-liable group"
can be by metabolic and/or chemical processes and can occur in one step
or through a series of two or more steps. Representative examples of a
"metabolically-labile group" include, but are not limited to,
--C(═O)O--R4d (thus, together with the nitrogen forms a
carbamate), --C(═O)--R4d (together with the nitrogen forms an
amide), and the like, wherein R4d is C1-18 alkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl each optionally substituted
with 1, 2, 3, 4, or 5 substituents selected independently from the group
consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl,
C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6
alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6
alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino,
C1-6 alkylamino, C2-4 dialkylamino, carbo-C1-6-alkoxy,
carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8
dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6
haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6
haloalkylsulfonyl, haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl,
and sulfonamide. In some embodiments, the "metabolically-labile group" is
C1-12 acyl, carbo-C1-12-alkoxy, or C(═O)O-aryl, wherein the
C1-12 acyl, carbo-C1-12-alkoxy, and -C(═O)O-aryl is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected
independently from the group consisting of C1-5 acyloxy, C is
alkylcarboxamide, amino, C1-6 alkylamino, C2-3 dialkylamino,
C1-6 alkylimino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl,
C1-6 alkylthio, halogen, nitro, and phenyl. The
"metabolically-labile groups" illustrated are exemplary and are not
exhaustive, and one skilled in the art could prepare other known
varieties of groups. In some cases, a "metabolically-labile group" (i.e.,
R4a) can serve to improve efficacy or safety through improved oral
bioavailability, or pharmacodynamic half-life, etc.

[0055] The term "pharmaceutical composition" is intended to mean a
composition comprising at least one active ingredient; including but not
limited to, salts, solvates and hydrates of compounds of Formula (Ia);
whereby the composition is amenable to investigation for a specified,
efficacious outcome in a mammal (for example, without limitation, a
human). Those of ordinary skill in the art will understand and appreciate
the techniques appropriate for determining whether an active ingredient
has a desired efficacious outcome based upon the needs of the artisan.

[0056] The term "prodrug" as used herein refers to any compound that when
administered to a biological system (e.g., in vivo in an individual, and
the like) generates a compound of Formula (Ia), wherein R4a is H, as
a result of chemical reaction(s), enzyme catalyzed chemical reaction(s),
and/or metabolic chemical reaction(s). In some embodiments, compounds of
the present invention can be converted to "pro-drugs." In some
embodiments, "pro-drugs" refer to compounds that have been modified with
specific chemical groups known in the art and when administered into an
individual these groups undergo biotransformation to give the parent
compound. Pro-drugs can thus be viewed as compounds of the invention
containing one or more specialized non-toxic protective groups used in a
transient manner to alter or to eliminate a property of the compound. In
one general aspect, the "pro-drug" approach is utilized to facilitate
oral absorption. A thorough discussion is provided in T. Higuchi and V.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series; and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press,
1987, both of which are hereby incorporated by reference in their
entirety.

[0057] The term "therapeutically effective amount" is intended to mean the
amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal, individual
or human that is being sought by a researcher, veterinarian, medical
doctor or other clinician, which includes one or more of the following:

[0058] (1) Preventing the disease; for example, preventing a disease,
condition or disorder in an individual that may be predisposed to the
disease, condition or disorder but does not yet experience or display the
pathology or symptomatology of the disease,

[0059] (2) Inhibiting the disease; for example, inhibiting a disease,
condition or disorder in an individual that is experiencing or displaying
the pathology or symptomatology of the disease, condition or disorder
(i.e., arresting further development of the pathology and/or
symptomatology), and

[0060] (3) Ameliorating the disease; for example, ameliorating a disease,
condition or disorder in an individual that is experiencing or displaying
the pathology or symptomatology of the disease, condition or disorder
(i.e., reversing the pathology and/or symptomatology).

[0061] Chemical Group, Moiety or Radical:

[0062] The term directly preceeding the chemical group beginning with "C"
followed directly by a subscript number or a subscript range of numbers
refers to the number of carbons associated with the chemical group. For
example, the term "C1-6" in the chemical group "C1-6 alkyl"
refers to an alkyl group containing one, two, three, four, five, or six
carbons, and all possible isomers.

[0063] The term "C1-12 acyl" denotes a C1-12 alkyl radical
attached to a carbonyl wherein alkyl has the same definition as described
herein, some embodiments are when acyl is C1-6 acyl, some
embodiments are when acyl is C1-5 acyl; some examples include, but
are not limited to, acetyl, propionyl, n-butanoyl, iso-butanoyl,
sec-butanoyl, t-butanoyl (i.e., pivaloyl), pentanoyl and the like.

[0064] The term "C1-12 acyloxy" denotes an acyl radical attached to
an oxygen atom wherein acyl has the same definition has described herein;
some embodiments are when acyloxy is acyloxy, some embodiments are when
acyloxy is C1-10 acyloxy, some embodiments are when acyloxy is
C1-8 acyloxy, some embodiments are when acyloxy is C1-6
acyloxy, some embodiments are when acyloxy is C1-5 acyloxy, some
embodiments are when acyloxy is C1-4 acyloxy, some embodiments are
when acyloxy is C10-12 acyloxy, some embodiments are when acyloxy is
C8-10 acyloxy. Some examples include, but are not limited to,
acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy,
t-butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,
nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy, and the like.

[0065] The term "C2-6 alkenyl" denotes a radical containing 2 to 6
carbons wherein at least one carbon-carbon double bond is present, some
embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and
some embodiments have 2 carbons. Both E and Z isomers are embraced by the
term "alkenyl." Furthermore, the term "alkenyl" includes di- and
tri-alkenyls. Accordingly, if more than one double bond is present then
the bonds may be all E or Z or a mixtures of E and Z. Examples of an
alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,
2,4-hexadienyl and the like.

[0066] The term "C1-6 alkoxy" as used herein denotes an alkyl
radical, as defined herein, attached directly to an oxygen atom. Examples
include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,
iso-butoxy, sec-butoxy and the like.

[0067] The term "C1-6 alkoxycarbonylamino" denotes the group
represented by the formula:

##STR00003##

wherein C1-6 alkyl has the same definition as found herein. Examples
of C1-6 alkoxycarbonylamino include methoxycarbonylamino,
ethoxycarbonylamino, isopropoxycarbonylamino, propoxycarbonylamino,
tert-butoxycarbonylamino, butoxycarbonylamino, and the like.

[0068] The term "C1-8 alkyl" denotes a straight or branched carbon
radical containing 1 to 8 carbons, some embodiments are 1 to 6 carbons,
some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons,
and some embodiments are 1 or 2 carbons. Examples of an alkyl include,
but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl,
1-methylbutyl [i.e., --CH(CH3)CH2CH2CH3],
2-methylbutyl [i.e., --CH2CH(CH3)CH2CH3], n-hexyl and
the like.

[0069] The term "C1-6 alkylcarboxamido" or "C1-6
alkylcarboxamide" denotes a single C1-6 alkyl group attached to the
nitrogen of an amide group, wherein alkyl has the same definition as
found herein. The C1-6 alkylcarboxamido may be represented by the
following:

[0070] The term "C1-4 alkylene" refers to a C1-4 divalent
straight carbon group containing 1 to 4 carbons, some embodiments are 1
to 3 carbons, some embodiments are 1 to 2 carbons. In some embodiments
alkylene refers to, for example, --CH2--, --CH2CH2--,
--CH2CH2CH2--, --CH2CH2CH2CH2--, and
the like.

[0071] The term "C1-6 alkylsulfinyl" denotes a C1-6 alkyl
radical attached to a sulfoxide radical of the formula: --S(O)-- wherein
the alkyl radical has the same definition as described herein. Examples
include, but are not limited to, methylsulfinyl, ethylsulfinyl,
n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,
iso-butylsulfinyl, t-butylsulfinyl, and the like.

[0072] The term "C1-6 alkylsulfonamide" refers to the groups shown
below:

##STR00005##

wherein C1-6 alkyl has the same definition as described herein.

[0073] The term "C1-6 alkylsulfonyl" denotes a C1-6 alkyl
radical attached to a sulfone radical of the formula: --S(O)2--
wherein the alkyl radical has the same definition as described herein.
Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,
iso-butylsulfonyl, t-butylsulfonyl, and the like.

[0074] The term "C1-6 alkylthio" denotes a C1-6 alkyl radical
attached to a sulfide of the formula: --S-- wherein the alkyl radical has
the same definition as described herein. Examples include, but are not
limited to, methylsulfanyl (i.e., CH3S--), ethylsulfanyl,
n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,
iso-butylsulfanyl, t-butylsulfanyl, and the like.

[0075] The term "C1-6 alkylthiocarboxamide" denotes a thioamide of
the following formulae:

##STR00006##

wherein C1-4 alkyl has the same definition as described herein.

[0076] The term "C1-6 alkylureyl" denotes the group of the formula:
--NC(O)N-- wherein one or both of the nitrogens are substituted with the
same or different C1-6 alkyl group wherein alkyl has the same
definition as described herein. Examples of an alkylureyl include, but
are not limited to, CH3NHC(O)NH--, NH2C(O)NCH3--,
(CH3)2NC(O)NH--, (CH3)2NC(O)NH--,
(CH3)2NC(O)NCH3--, CH3CH2NHC(O)NH--,
CH3CH2NHC(O)NCH3--, and the like.

[0077] The term "C2-6 alkynyl" denotes a radical containing 2 to 6
carbons and at least one carbon-carbon triple bond, some embodiments are
2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments
have 2 carbons. Examples of an alkynyl include, but are not limited to,
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,
3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term "alkynyl" includes
di- and tri-ynes.

[0078] The term "amino" denotes the group --NH2.

[0079] The term "C1-6 alkylamino" denotes one alkyl radical attached
to an amino radical wherein the alkyl radical has the same meaning as
described herein. Some examples include, but are not limited to,
methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,
sec-butylamino, iso-butylamino, t-butylamino, and the like. Some
embodiments are "C1-2 alkylamino."

[0080] The term "aryl" denotes a 6- to 12-membered mono- or bicyclic ring
system containing only ring carbons wherein at least one ring is
aromatic. Examples include phenyl, 1,2,3,4-tetrahydro-naphthalen-1-yl,
1,2,3,4-tetrahydro-naphthalen-2-yl, 5,6,7,8-tetrahydro-naphthalen-1-yl,
5,6,7,8-tetrahydro-naphthalen-2-yl, indan-4-yl, naphtha-1-yl,
naphtha-2-yl, and the like.

[0081] The term "arylalkyl" defines a C1-C4 alkylene, such as
--CH2--, --CH2CH2-- and the like, which is further
substituted with an aryl group. Examples of an "arylalkyl" include
benzyl, phenethylene and the like.

[0082] The term "arylcarboxamido" denotes a single aryl group attached to
the nitrogen of an amide group, wherein aryl has the same definition as
found herein. The example is N-phenylcarboxamide.

[0083] The term "arylureyl" denotes the group --NC(O)N-- where one of the
nitrogens are substituted with an aryl.

[0084] The term "benzyl" denotes the group --CH2C6H5.

[0085] The term "bicyclic" refers to two C4-7 cyclalkyl groups that
share two ring carbons thus forming either a fused or bridged ring.
Bicyclic examples include, but not limited to, bicyclo[1.1.1]pentyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, and the like.

[0086] The term "carbo-C1-6-alkoxy" refers to a C1-6 alkyl ester
of a carboxylic acid, wherein the alkyl group is as defined herein.
Examples include, but are not limited to, carbomethoxy, carboethoxy,
carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy,
carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy,
carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.

[0087] The term "carboxamide" refers to the group --CONH2.

[0088] The term "carboxy" or "carboxyl" denotes the group --CO2H;
also referred to as a carboxylic acid group.

[0089] The term "cyano" denotes the group --CN.

[0090] The term "C4-7 cycloalkenyl" denotes a non-aromatic ring
radical containing 4 to 7 ring carbons and at least one double bond; some
embodiments contain 4 to 6 carbons; some embodiments contain 4 to 5
carbons; some embodiments contain 4 carbons. Examples include
cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.

[0092] The term "C3-7 cycloalkylcarbonyl" denotes a C3-7
cycloalkyl group, as described herein, bonded to the carbon of a carbonyl
group (i.e., --C(═O)--). Examples of the C3-7 cycloalkylcarbonyl
group include, but not limited to, cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, and the like.

[0093] The term "C3-6 cycloalkylene" refers to a divalent cycloalkyl
radical, where cycloalkyl is as defined herein, containing 3 to 6
carbons; some embodiments contain 3 to 5 carbons; some embodiments
contain 3 to 4 carbons. In some embodiments, the C3-6 cycloalkylene
group has the two bonding groups on the same ring carbon, for example:

##STR00007##

In some embodiments, the C3-6 cycloalkylene group has the two
bonding groups on different ring carbons. It is understood that when the
two groups of the C3-6 cycloalkylene group are on different ring
carbons they may be cis or trans or mixtures thereof with respect to each
other.

[0094] The term "C2-8 dialkylamino" denotes an amino substituted with
two of the same or different C1-4 alkyl radicals wherein alkyl
radical has the same definition as described herein. Some examples
include, but are not limited to, dimethylamino, methylethylamino,
diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino,
ethylisopropylamino, dipropylamino, propylisopropylamino and the like.
Some embodiments are "C2-4 dialkylamino."

[0095] The term "C2-8 dialkylcarboxamido" or "C2-8
dialkylcarboxamide" denotes two alkyl radicals, that are the same or
different, attached to an amide group, wherein alkyl has the same
definition as described herein. A C2-8 dialkylcarboxamido may be
represented by the following groups:

##STR00008##

wherein C1-4 has the same definition as described herein. Examples
of a dialkylcarboxamide include, but are not limited to,
N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,
N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

[0096] The term "C2-8 dialkylsulfonamide" refers to one of the
following groups shown below:

##STR00009##

[0097] wherein C1-4 has the same definition as described herein, for
example but are not limited to, methyl, ethyl, n-propyl, isopropyl, and
the like.

[0098] The term "C2-8 dialkylthiocarboxamido" or "C2-8
dialkylthiocarbox-amide" denotes two alkyl radicals, that are the same or
different, attached to a thioamide group, wherein alkyl has the same
definition as described herein. A C2-8 diallylthiocarboxamido or
C2-8 dialkylthiocarboxamide may be represented by the following
groups:

##STR00010##

Examples of a diallylthiocarboxamide include, but are not limited to,
N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and the
like.

[0099] The term "formyl" refers to the group --CHO.

[0100] The term "C1-6 haloalkoxy" denotes a C1-6 haloalkyl, as
defined herein, which is directly attached to an oxygen atom. Examples
include, but are not limited to, difluoromethoxy, trifluoromethoxy,
2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

[0101] The term "C1-6 haloalkyl" denotes an C1-6 alkyl group,
defined herein, wherein the alkyl is substituted with one halogen up to
fully substituted and a fully substituted C1-6 haloalkyl can be
represented by the formula CnL2n+1 wherein L is a halogen and
"n" is 1, 2, 3, 4, 5 or 6; when more than one halogen is present then
they may be the same or different and selected from the group consisting
of F, Cl, Br and I, preferably F. Examples of haloalkyl groups include,
but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the
like.

[0102] The term "C1-6 haloalkylcarboxamide" denotes an C1-6
alkylcarboxamide group, defined herein, wherein the alkyl is substituted
with one halogen up to fully substituted represented by the formula
CnL2n+1 wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6.
When more than one halogen is present they may be the same or different
and selected from the group consisting of F, Cl, Br and I, preferably F.

[0103] The term "C1-6 haloalkylsulfinyl" denotes a C1-6
haloalkyl radical attached to a sulfoxide group of the formula: --S(O)--
wherein the haloalkyl radical has the same definition as described
herein. Examples include, but are not limited to,
trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,
2,2-difluoroethylsulfinyl and the like.

[0104] The term "C1-6 haloalkylsulfonyl" denotes a C1-6
haloalkyl radical attached to a sulfone group of the formula:
--S(O)2-- wherein haloalkyl has the same definition as described
herein. Examples include, but are not limited to,
trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,
2,2-difluoroethylsulfonyl and the like.

[0105] The term "C1-6 haloalkylthio" denotes a C1-6 haloalkyl
radical directly attached to a sulfur wherein the haloalkyl has the same
meaning as described herein. Examples include, but are not limited to,
trifluoromethylthio (i.e., CF3S--, also referred to as
trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio
and the like. The term "halogen" or "halo" denotes to a fluoro, chloro,
bromo or iodo group.

[0106] The term "heteroaryl" denotes a 6- to 12-membered mono- or bicyclic
ring system wherein at least one ring atom is a heteroatom and at least
one ring is aromatic. Examples of a heteroatom include, O, S, N and the
like. In some embodiments, N is optionally substituted, for example, H,
or C1-4 alkyl. Examples of heteroaryl groups include, but are not
limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl,
triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl,
isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolyl, indolyl,
1H-benzoimidazol-2-yl, benzo[1,3]dioxol-5-yl,
3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, 2,3-dihydro-benzofurn-7-yl,
2,3-dihydro-indol-1-yl, and the like. Other examples include, but are not
limited to, those in TABLE 1, TABLE 2, and the like.

[0107] The term "heterobicyclic" denotes a non-aromatic bicyclic ring, as
described herein, wherein 1, 2, or 3 ring carbons are replaced with a
heteroatom selected from, but are not limited to, the group consisting of
O, S, S(═O), S(═O)2, and NH, wherein the nitrogen can be
optionally substituted, and 1 or 2 ring carbons can be optionally
substituted with oxo or thiooxo thus together form a carbonyl or
thiocarbonyl group respectively. Examples of a heterobicyclic group
include, but are not limited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,
7-aza-bicyclo[2.2.1]hept-7-yl, and the like.

[0108] The term "heterocyclic" denotes a 3- to 12-membered mono- or
bicyclic non-aromatic ring system wherein at least one ring atom is a
heteroatom. In some embodiments, heteroatom is selected from, but are not
limited to, the group consisting of O, S, S(═O), S(═O)2, NH,
wherein the N of the heterocyclic can be optionally substituted as
described herein, in some embodiments, the nitrogen is optionally
substituted with C1-4 acyl or C1-4 alkyl, and ring carbon atoms
optionally substituted with oxo or a thiooxo thus forming a carbonyl or
thiocarbonyl group. The heterocyclic group can be bonded at any available
ring atom, for example, ring carbon, ring nitrogen, and the like. In some
embodiments, the heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered
containing ring. Examples of a heterocyclic group include, but are not
limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,
piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,
piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl,
pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl,
thiomorpholin-4-yl, [1,4]oxazepan-4-yl,
1,1-dioxo-1λ6-thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl,
azepan-3-yl, azepan-4-yl, octahydro-quinolin-1-yl,
octahydro-isoquinolin-2-yl, and the like.

[0109] The term "hydroxyl" refers to the group --OH.

[0110] The term "nitro" refers to the group --NO2.

[0111] As used herein, the term "oxo" refers to the substituent ═O,
accordingly, when a carbon is substituted by an oxo group the new group
resulting from the carbon and oxo together is a carbonyl group.

[0112] The term "phenoxy" refers to the group C6H5O--.

[0113] The term "phenyl" refers to the group C6H5--.

[0114] The term"sulfonic acid" refers to the group --SO3H.

[0115] The term "thiol" denotes the group --SH.

Compounds of the Invention:

[0116] One aspect of the present invention pertains to certain compounds
as shown in Formula (Ia):

##STR00011##

[0117] or a pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein R1, R2, R3, R5, R6, R7, R8, V,
W, Q, and Z have the same definitions as described herein, supra and
infra.

[0118] One aspect of the present invention pertains to certain compounds
as shown in Formula (Ia) wherein:

[0120] In some embodiments, the present invention pertains to compounds of
Formula (Ia), as described herein, that are isolated.

[0121] In some embodiments, the present invention pertains to compounds of
Formula (Ia), as described herein, that are isolated outside the body of
an individual.

[0122] In some embodiments, the present invention pertains to compounds of
Formula (Ia), as described herein, that are isolated outside the body of
an individual. In some embodiments, isolated compounds of Formula (Ia)
have a purity of greater than about 0.1%, about 1%, about 5%, about 10%,
about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about
50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 95%, about 98%, or about 99%.

[0123] In some embodiments, the present invention pertains to compounds of
Formula (Ia), as described herein, or a pharmaceutically acceptable salt,
hydrate, solvate, or N-oxide thereof.

[0124] It is appreciated that certain features of the invention, which
are, for clarity, described in the context of separate embodiments, may
also be provided in combination in a single embodiment. Conversely,
various features of the invention, which are, for brevity, described in
the context of a single embodiment, may also be provided separately or in
any suitable subcombination. All combinations of the embodiments
pertaining to the chemical groups represented by the variables (e.g.,
R1, R2, R3, R5, R6, R7, R8, V, W, Q,
Z, etc.) contained within the generic chemical formulae described herein
[e.g. (Ia), (Ic), (Ie), etc.] are specifically embraced by the present
invention just as if they were explicitly disclosed, to the extent that
such combinations embrace compounds that result in stable compounds (ie.,
compounds that can be isolated, characterized and tested for biological
activity). In addition, all subcombinations of the chemical groups listed
in the embodiments describing such variables, as well as all
subcombinations of uses and medical indications described herein, are
also specifically embraced by the present invention just as if each of
such subcombination of chemical groups and subcombination of uses and
medical indications were explicitly disclosed herein.

[0125] As used herein, "substituted" indicates that at least one hydrogen
atom of the chemical group is replaced by a non-hydrogen substituent or
group, the non-hydrogen substituent or group can be monovalent or
divalent. When the substituent or group is divalent, then it is
understood that this group is further substituted with another
substituent or group. When a chemical group herein is "substituted" it
may have up to the full valance of substitution; for example, a methyl
group can be substituted by 1, 2, or 3 substituents, a methylene group
can be substituted by 1 or 2 substituents, a phenyl group can be
substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be
substituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.
Likewise, "substituted with one or more substituents" refers to the
substitution of a group with one substituent up to the total number of
substituents physically allowed by the group. Further, when a group is
substituted with more than one group they can be identical or they can be
different.

[0126] Compounds of the invention can also include tautomeric forms, such
as keto-enol tautomers, and the like. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution. It is understood that the various tautomeric forms are
within the scope of the compounds of the present invention.

[0127] Compounds of the invention can also include all isotopes of atoms
occurring in the intermediates and/or final compounds. Isotopes include
those atoms having the same atomic number but different mass numbers. For
example, isotopes of hydrogen include deuterium and tritium.

[0128] It is understood and appreciated that compounds of the present
invention may have one or more chiral centers, and therefore can exist as
enantiomers and/or diastereomers. The invention is understood to extend
to and embrace all such enantiomers, diastereomers and mixtures thereof,
including but not limited, to racemates. Accordingly, some embodiments of
the present invention pertain to compounds of the present invention that
are R enantiomers. Further, some embodiments of the present invention
pertain to compounds of the present invention that are S enantiomers. In
examples where more than one chiral center is present, then, some
embodiments of the present invention include compounds that are RS or SR
enantiomers. In further embodiments, compounds of the present invention
are RR or SS enantiomers. It is understood that compounds of the present
invention are intended to represent all possible individual enantiomers
and mixtures thereof just as if each had been individually named with the
structure provided, unless stated or shown otherwise.

[0129] Some embodiments of the present invention pertain to certain
compounds as shown in the following Formula (Ic):

##STR00012##

[0130] wherein each variable in Formula (Ic) has the same meaning as
described herein, supra and infra.

[0131] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ie):

##STR00013##

[0132] wherein each variable in Formula (Ie) has the same meaning as
described herein, supra and infra.

[0133] In some embodiments, V is O.

[0134] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ig):

##STR00014##

[0135] wherein each variable in Formula (Ig) has the same meaning as
described herein, supra and infra.

[0136] In some embodiments, W is --CH2CH2-- optionally
substituted with 1 to 2 substituents selected independently from the
group consisting of C1-3 alkyl and oxo.

[0137] In some embodiments, W is --CH2CH2--,
--CH2C(CH3)2--, or --CH2C(═O)--.

[0138] In some embodiment; W is --CH2CH2--.

[0139] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ii):

##STR00015##

[0140] wherein each variable in Formula (II) has the same meaning as
described herein, supra and infra.

[0141] In some embodiments, Z is absent.

[0142] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ik):

##STR00016##

[0143] wherein each variable in Formula (Ik) has the same meaning as
described herein, supra and infra.

[0144] In some embodiments, Z is --CH2-- or --CH2CH2--

[0145] In some embodiments, R1 is C1-6 alkyl.

[0146] In some embodiments, R1 is --CH3.

[0147] In some embodiments, R1 is H.

[0148] It is understood when R1 is H that tautomers are possible. It
is well understood and appreciated in the art that pyrazoles can exist in
various tautomeric forms. Two possible tautomeric forms are illustrated
below:

##STR00017##

[0149] It is further understood that tautomeric forms can also have
corresponding nomenclature for each represented tautomer, for example,
the pyrazol-3-yl groups in Formula (Im) and Formula (In) can be
represented by the general chemical names 1H-pyrazol-3-yl and
2H-pyrazol-3-yl respectively. Therefore, the present invention includes
all tautomers and the various nomenclature designations.

[0150] In some embodiments, R2 is H.

[0151] In some embodiments, R3 is H or halogen.

[0152] In some embodiments, R3 is H, Cl, or Br.

[0153] In some embodiments, Q is --NR4aR4b.

[0154] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ip):

##STR00018##

[0155] wherein each variable in Formula (Ip) has the same meaning as
described herein, supra and infra.

[0156] In some embodiments, R4a is H,

[0157] Some embodiments of the present invention pertain to certain
compounds as shown in Formula (Ir):

##STR00019##

[0158] wherein each variable in Formula (Ir) has the same meaning as
described herein, supra and infra.

[0173] In some embodiments, R4c is C1-6 alkyl, C1-12 acyl,
heterocyclyl, or heteroaryl each optionally substituted with 1 to 2
substituents selected independently from the group consisting of
C1-8 alkyl, C2-8 dialkylamino, and heterocyclyl.

[0174] In some embodiments, Q is --OH, --OCH3,
--OC(═O)CH2-morpholin-4-yl,
--OC(═O)CH2N(CH3)2,
--OC(═O)CH2-pyrrolidin-1-yl, or 1-methyl-piperidin-4-yloxy.

[0175] In some embodiments, R5 is H.

[0176] In some embodiments, R6 is H.

[0177] In some embodiments, R7 is H.

[0178] In some embodiments, R5, R6 and R7 are each H.

[0179] In some embodiments, R8 is aryl, C3-10 cycloalkyl, or
heteroaryl each optionally substituted with substituents selected
independently from the group consisting of C1-6 alkoxy, C1-6
alkyl, cyano, halogen, C1-6 haloalkoxy, and C1-6 haloalkyl.

[0180] In some embodiments, R8 is phenyl, cyclopropyl, or heteroaryl
each optionally substituted with substituents selected independently from
the group consisting of C1-6 alkoxy, C1-6 alkyl, cyano,
halogen, C1-6 haloalkoxy, and C1-6 haloalkyl.

[0181] In some embodiments, R8 is phenyl, cyclopropyl, or isoxazolyl
each optionally substituted with substituents selected independently from
the group consisting of C1-6 alkoxy, C1-6 alkyl, cyano,
halogen, C1-6 haloalkoxy, and C1-6 haloalkyl.

[0182] In some embodiments, R8 is phenyl, cyclopropyl, or isoxazolyl
and each optionally substituted with substituents selected independently
from the group consisting of --CH3, Br, CF3, --OCH3, Cl,
F, --OCF3, and cyano.

[0186] wherein the 5-membered heteroaryl is bonded at any available
position of the ring, for example, a imidazolyl ring can be bonded at one
of the ring nitrogens (i.e., imidazol-1-yl group) or at one of the ring
carbons (i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group).

[0187] In some embodiments, heteroaryl is a 6-membered heteroaryl, for
example, a 6-membered heteroaryl as shown in TABLE 2:

TABLE-US-00002
TABLE 2
##STR00026##
##STR00027##

[0188] wherein the heteroaryl group is bonded at any ring carbon.

[0189] Some embodiments of the present invention pertain to certain
compounds of Formula (IIa):

##STR00028##

[0190] wherein:

[0191] W is --CH2CH2-- optionally substituted with 1 to 2
substituents selected independently from the group consisting of
C1-3 alkyl and oxo;

[0234] It is understood that the present invention embraces each
diastereomer, each enantiomer and mixtures thereof of each compound and
generic Formulae disclosed herein just as if they were each individually
disclosed with the specific stereochemical designation for each chiral
atom, for example carbon. Separation of the individual isomers (such as,
chiral HPLC, recrystallization of diastereomeric mixture, and the like)
or selective synthesis (such as, enantiomeric selective synthesis, and
the like) of the individual isomers is accomplished by application of
various methods which are well known to practitioners in the art.

[0235] The compounds of the Formula (Ia) of the present invention can be
prepared according to the general synthetic schemes in FIGS. 1 through 8
as well as relevant published literature procedures that are used by one
skilled in the art. Exemplary reagents and procedures for these reactions
appear hereinafter in the working Examples. Protection and deprotection
may be carried out by procedures generally known in the art (see, for
example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic
Synthesis, 3rd Edition, 1999 [Wiley]; incorporated herein by
reference in its entirety).

Indications and Methods of Treatment

[0236] In addition to the foregoing beneficial uses for the modulators of
5-HT2A receptor activity disclosed herein, the compounds disclosed
herein are believed to be useful in the treatment of several additional
diseases and disorders, and in the amelioration of symptoms thereof.
Without limitation, these include the following:

[0238] Antiplatelet agents (antiplatelets) are prescribed for a variety of
conditions. For example, in coronary artery disease they are used to help
prevent myocardial infarction or stroke in patients who are at risk of
developing obstructive blood clots (e.g., coronary thrombosis).

[0239] In a myocardial infarction (heart attack), the heart muscle does
not receive enough oxygen-rich blood as a result of a blockage in the
coronary blood vessels. If taken while an attack is in progress or
immediately afterward (preferably within 30 minutes), antiplatelets can
reduce the damage to the heart.

[0240] A transient ischemic attack ("TIA" or "mini-stroke") is a brief
interruption of oxygen flow to the brain due to decreased blood flow
through arteries, usually due to an obstructing blood clot. Antiplatelet
drugs have been found to be effective in preventing TIAs.

[0241] Angina is a temporary and often recurring chest pain, pressure or
discomfort caused by inadequate oxygen-rich blood flow (ischemia) to some
parts of the heart. In patients with angina, antiplatelet therapy can
reduce the effects of angina and the risk of myocardial infarction.

[0242] Stroke is an event in which the brain does not receive enough
oxygen-rich blood, usually due to blockage of a cerebral blood vessel by
a blood clot. In high-risk patients, taking antiplatelets regularly has
been found to prevent the formation of blood clots that cause first or
second strokes.

[0243] Angioplasty is a catheter based technique used to open arteries
obstructed by a blood clot. Whether or not stenting is performed
immediately after this procedure to keep the artery open, antiplatelets
can reduce the risk of forming additional blood clots following the
procedure(s).

[0244] Coronary bypass surgery is a surgical procedure in which an artery
or vein is taken from elsewhere in the body and grafted to a blocked
coronary artery, rerouting blood around the blockage and through the
newly attached vessel. After the procedure, antiplatelets can reduce the
risk of secondary blood clots.

[0245] Atrial fibrillation is the most common type of sustained irregular
heart rhythm (arrythmia). Atrial fibrillation affects about two million
Americans every year. In atrial fibrillation, the atria (the heart's
upper chambers) rapidly fire electrical signals that cause them to quiver
rather than contract normally. The result is an abnormally fast and
highly irregular heartbeat. When given after an episode of atrial
fibrillation, antiplatelets can reduce the risk of blood clots forming in
the heart and traveling to the brain (embolism).

[0248] 5-HT2A inverse antagonists can increase circulating
adiponectin in patients, suggesting that they would also be useful in
protecting patients against indications that are linked to adiponectin,
for example, myocardial ischemia reperfusion injury and artherosclerosis
(see Nomura, Shosaku, et al. Blood Coagulation and Fibrinolysis 2005, 16,
423-428).

[0249] The 5-HT2A inverse agonists disclosed herein provide
beneficial improvement in microcirculation to patients in need of
antiplatelet therapy by antagonizing the vasoconstrictive products of the
aggregating platelets in, for example and not limited to the indications
described above. Accordingly, in some embodiments, the present invention
provides methods for reducing platelet aggregation in a patient in need
thereof comprising administering to the patient a composition comprising
a 5-HT2A inverse agonist disclosed herein. In further embodiments,
the present invention provides methods for treating coronary artery
disease, myocardial infarction, transient ischemic attack, angina,
stroke, atrial fibrillation, or a symptom of any of the foregoing in a
patient in need of the treatment, comprising administering to the patient
a composition comprising a 5-HT2A inverse agonist disclosed herein.

[0250] In further embodiments, the present invention provides methods for
reducing risk of blood clot formation in an angioplasty or coronary
bypass surgery patient, or a patient suffering from atrial fibrillation,
comprising administering to the patient a composition comprising a
5-HT2A inverse agonist disclosed herein at a time where such risk
exists.

[0251] One aspect of the present invention provides a therapeutic agent
for treating indications associated with the pathophysiology of platelet
aggregation used in combination with compounds of the present invention
as disclosed herein. Accordingly, compounds of the present invention can
be used alone or in combination with other therapeutic agent(s), such as,
thromboxane A2 blocker (aspirin and the like), and ADP-mediated platelet
aggregation inhibitor (ticlopidine, clopidogrel, and the like) either
administered together or separately.

[0252] 2. Asthma

[0253] 5-HT (5-hydroxytryptamine) has been linked to the pathophysiology
of acute asthma (see Cazzola, M. and Matera, M. G., TIPS, 2000, 21, 13;
and De Bie, J. J. et al., British J. Pharm., 1998, 124, 857-864). The
compounds of the present invention disclosed herein are useful in the
treatment of asthma, and the treatment of the symptoms thereof.
Accordingly, in some embodiments, the present invention provides methods
for treating asthma in a patient in need of the treatment, comprising
administering to the patient a composition comprising a 5-HT2A
inverse agonist disclosed herein. In further embodiments, methods are
provided for treating a symptom of asthma in a patient in need of the
treatment, comprising administering to the patient a composition
comprising a 5-HT2A inverse agonist disclosed herein.

[0256] Agitation is a common occurrence in the elderly and often
associated with dementia such as those caused by Alzheimer's disease,
Lewy body, Parkinson's, and Huntington's, which are degenerative diseases
of the nervous system and by diseases that affect blood vessels, such as
stroke, or multi-infarct dementia, which is caused by multiple strokes in
the brain can also induce dementia. Alzheimer's disease accounts for
approximately 50 to 70% of all dementias (See Koss E, et al., (1997),
Assessing patterns of agitation in Alzheimer's disease patients with the
Cohen-Mansfield Agitation Inventory. The Alzheimer's Disease Cooperative
Study. Alzheimer Dis Assoc Disord 11(suppl 2):S45-S50).

[0257] An estimated five percent of people aged 65 and older and up to 20
percent of those aged 80 and older are affected by dementia; of these
sufferers, nearly half exhibit behavioral disturbances, such as
agitation, wandering and violent outbursts.

[0258] Agitated behaviors can also be manifested in cognitively intact
elderly people and by those with psychiatric disorders other than
dementia.

[0259] Agitation is often treated with antipsychotic medications such as
haloperidol in nursing home and other assisted care settings. There is
emerging evidence that agents acting at the 5-HT2A receptors in the
brain have the effects of reducing agitation in patients, including
Alzheimer's dementia (See Katz, I. R., et al., J Clin Psychiatry 1999
February, 60(2):107-115; and Street, J. S., et al., Arch Gen Psychiatry
2000 October, 57(10):968-976).

[0260] The compounds of the invention disclosed herein are useful for
treating agitation and symptoms thereof. Thus, in some embodiments, the
present invention provides methods for treating agitation in a patient in
need of such treatment comprising administering to the patient a
composition comprising a 5-HT2A inverse agonist disclosed herein. In
some embodiments, the agitation is due to a psychiatric disorder other
than dementia. In some embodiments, the present invention provides
methods for treatment of agitation or a symptom thereof in a patient
suffering from dementia comprising administering to the patient a
composition comprising a 5-HT2A inverse agonist disclosed herein. In
some embodiments of such methods, the dementia is due to a degenerative
disease of the nervous system, for example and without limitation,
Alzheimers disease, Lewy body, Parkinson's disease, and Huntington's
disease, or dementia due to diseases that affect blood vessels,
including, without limitation, stroke and multi-infarct dementia. In some
embodiments, methods are provided for treating agitation or a symptom
thereof in a patient in need of such treatment, where the patient is a
cognitively intact elderly patient, comprising administering to the
patient a composition comprising a 5-HT2A inverse agonist disclosed
herein.

[0261] 4. Add-on Therapy to Haloperidol in the Treatment of Schizophrenia
and Other Disorders:

[0262] Schizophrenia is a psychopathic disorder of unknown origin, which
usually appears for the first time in early adulthood and is marked by a
number of characteristics, psychotic symptoms, progression, phasic
development and deterioration in social behavior and professional
capability in the region below the highest level ever attained.
Characteristic psychotic symptoms are disorders of thought content
(multiple, fragmentary, incoherent, implausible or simply delusional
contents or ideas of persecution) and of mentality (loss of association,
flight of imagination, incoherence up to incomprehensibility), as well as
disorders of perceptibility (hallucinations), of emotions (superficial or
inadequate emotions), of self-perception, of intentions and impulses, of
interhuman relationships, and finally psychomotoric disorders (such as
catatonia). Other symptoms are also associated with this disorder. (See,
American Statistical and Diagnostic Handbook).

[0263] Haloperidol (Haldol) is a potent dopamine D2 receptor
antagonist. It is widely prescribed for acute schizophrenic symptoms, and
is very effective for the positive symptoms of schizophrenia. However,
Haldol is not effective for the negative symptoms of schizophrenia and
may actually induce negative symptoms as well as cognitive dysfunction.
In accordance with some methods of the invention, adding a 5-HT2A
inverse agonist concomitantly with Haldol will provide benefits including
the ability to use a lower dose of Haldol without losing its effects on
positive symptoms, while reducing or eliminating its inductive effects on
negative symptoms, and prolonging relapse to the patient's next
schizophrenic event.

[0264] Haloperidol is used for treatment of a variety of behavioral
disorders, drug induced psychosis, excitative psychosis, Gilles de la
Tourette's syndrome, manic disorders, psychosis (organic and NOS),
psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS).
Further uses include in the treatment of infantile autism, huntington's
chorea, and nausea and vomiting from chemotherapy and chemotherapeutic
antibodies. Administration of 5-HT2A inverse agonists disclosed
herein with haloperidol also will provide benefits in these indications.

[0267] In some embodiments, the present invention provides methods for
treating infantile autism, huntington's chorea, or nausea and vomiting
from chemotherapy or chemotherapeutic antibodies comprising administering
to the patient a dopamine D2 receptor antagonist and a 5-HT2A
inverse agonist disclosed herein.

[0268] In some embodiments, the present invention provides methods for
treating infantile autism, huntington's chorea, or nausea and vomiting
from chemotherapy or chemotherapeutic antibodies comprising administering
to the patient haloperidol and a 5-HT2A inverse agonist disclosed
herein.

[0269] In further embodiments, the present invention provides methods for
treating schizophrenia in a patient in need of the treatment comprising
administering to the patient a dopamine D2 receptor antagonist and a
5-HT2A inverse agonist disclosed herein. Preferably, the dopamine
D2 receptor antagonist is haloperidol.

[0270] The administration of the dopamine D2 receptor antagonist can
be concomitant with administration of the 5-HT2A inverse agonist, or
they can be administered at different times. Those of skill in the art
will easily be able to determine appropriate dosing regimes for the most
efficacious reduction or elimination of deleterious haloperidol effects.
In some embodiments, haloperidol and the 5-HT2A inverse agonist are
administered in a single dosage form, and in other embodiments, they are
administered in separate dosage forms.

[0271] The present invention further provides methods of alleviating
negative symptoms of schizophrenia induced by the administration of
haloperidol to a patient suffering from schizophrenia, comprising
administering to the patient a 5-HT2A inverse agonist as disclosed
herein.

[0272] 5. Sleep Disorders

[0273] It is reported in the National Sleep Foundation's 2002 Sleep In
America Poll, more than one-half of the adults surveyed (58%) report
having experienced one or more symptoms of insomnia at least a few nights
a week in the past year. Additionally, about three in ten (35%) say they
have experienced insomnia-like symptoms every night or almost every
night.

[0274] The normal sleep cycle and sleep architecture can be disrupted by a
variety of organic causes as well as environmental influences. According
to the International Classification of Sleep Disorders, there are over 80
recognized sleep disorders. Of these, compounds of the present invention
are effective, for example, in any one or more of the following sleep
disorders (ICSD--International Classification of Sleep Disorders:
Diagnostic and Coding Manual. Diagnostic Classification Steering
Committee, American Sleep Disorders Association, 1990):

[0291] The effects of sleep deprivation are more than excessive daytime
sleepiness. Chronic insomniacs report elevated levels of stress, anxiety,
depression and medical illnesses (National Institutes of Health, National
Heart, Lung, and Blood Institute, Insomnia Facts Sheet, October 1995).
Preliminary evidence suggests that having a sleep disorder that causes
significant loss of sleep may contribute to increased susceptibility to
infections due to immunosuppression, cardiovascular complications such as
hypertension, cardiac arrhythmias, stroke, and myocardial infarction,
comprimised glucose tolerance, increased obesity and metabolic syndrome.
Compounds of the present invention are useful to prevent or alleviate
these complications by improving sleep quality.

[0292] The most common class of medications for the majority of sleep
disorders are the benzodiazepines, but the adverse effect profile of
benzodiazepines include daytime sedation, diminished motor coordination,
and cognitive impairments. Furthermore, the National Institutes of Health
Consensus conference on Sleeping Pills and Insomnia in 1984 have
developed guidelines discouraging the use of such sedative-hypnotics
beyond 4-6 weeks because of concerns raised over drug misuse, dependency,
withdrawal and rebound insomnia. Therefore, it is desirable to have a
pharmacological agent for the treatment of insomnia, which is more
effective and/or has fewer side effects than those currently used. In
addition, benzodiazepines are used to induce sleep, but have little to no
effect on the maintenance of sleep, sleep consolidation or slow wave
sleep. Therefore, sleep maintenance disorders are not currently well
treated.

[0293] Clinical studies with agents of a similar mechanism of action as
are compounds of the present invention have demonstrated significant
improvements on objective and subjective sleep parameters in normal,
healthy volunteers as well as patients with sleep disorders and mood
disorders [Sharpley A L, et al. Slow Wave Sleep in Humans: Role of
5-HT2A and 5HT2C Receptors. Neuropharmacology, 1994, Vol.
33(3/4):467-71; Winokur A, et al. Acute Effects of Mirtazapine on Sleep
Continuity and Sleep Architecture in Depressed Patients: A Pilot Study.
Soc of Biol Psych, 2000, Vol. 48:75-78; and Landolt H P, et al.
Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist on
EEG Power Spectra. Neuropsychopharmacology, 1999, Vol. 21(3):455-66].

[0294] Some sleep disorders are sometimes found in conjunction with other
conditions and accordingly those conditions are treatable by compounds of
Formula (Ia). For example, but not limited to, patients suffering from
mood disorders typically suffer from a sleep disorder that can be
treatable by compounds of Formula (Ia). Having one pharmacological agent
which treats two or more existing or potential conditions, as does the
present invention, is more cost effective, leads to better compliance and
has fewer side effects than taking two or more agents.

[0295] It is an object of the present invention to provide a therapeutic
agent for the use in treating Sleep Disorders. It is another object of
the present invention to provide one pharmaceutical agent, which may be
useful in treating two or more conditions wherein one of the conditions
is a sleep disorder. Compounds of the present invention described herein
may be used alone or in combination with a mild sleep inducer, such as, a
sedating antihistamine (diphenhydramine, chloropheniramine,
bromopheniramine and the like), GABA-A receptor modulators (Ambien,
Sonata, Indiplon, Gaboxadol, and the like), melatonin agonists (ML1
receptor agonist, such as Ramelteon and the like), sedating
antidepressants (such as a tricyclic antidepressant, doxepine and the
like), and benzodiazepines (diazepam and the like) and either
administered together or separately.

Sleep Architecture:

[0296] Sleep comprises two physiological states: Non rapid eye movement
(NREM) and rapid eye movement (REM) sleep. NREM sleep consists of four
stages, each of which is characterized by progressively slower brain wave
patterns, with the slower patterns indicating deeper sleep. So called
delta sleep, stages 3 and 4 of NREM sleep, is the deepest and most
refreshing type of sleep. Many patients with sleep disorders are unable
to adequately achieve the restorative sleep of stages 3 and 4. In
clinical terms, patients' sleep patterns are described as fragmented,
meaning the patient spends a lot of time alternating between stages 1 and
2 (semi-wakefulness) and being awake and very little time in deep sleep.
As used herein, the term "fragmented sleep architecture" means an
individual, such as a sleep disorder patient, spends the majority of
their sleep time in NREM sleep stages 1 and 2, lighter periods of sleep
from which the individual can be easily aroused to a Waking state by
limited external stimuli. As a result, the individual cycles through
frequent bouts of light sleep interrupted by frequent awakenings
throughout the sleep period. Many sleep disorders are characterized by a
fragmented sleep architecture. For example, many elderly patients with
sleep complaints have difficulty achieving long bouts of deep refreshing
sleep (NREM stages 3 and 4) and instead spend the majority of their sleep
time in NREM sleep stages 1 and 2.

[0297] In contrast to fragmented sleep architecture, as used herein the
term "sleep consolidation" means a state in which the number of NREM
sleep bouts, particularly Stages 3 and 4, and the length of those sleep
bouts are increased, while the number and length of waking bouts are
decreased. In essence, the architecture of the sleep disorder patient is
consolidated to a sleeping state with increased periods of sleep and
fewer awakenings during the night and more time is spent in slow wave
sleep (Stages 3 and 4) with fewer oscillation Stage 1 and 2 sleep.
Compounds of the present invention can be effective in consolidating
sleep patterns so that the patient with previously fragmented sleep can
now achieve restorative, delta-wave sleep for longer, more consistent
periods of time.

[0298] As sleep moves from stage 1 into later stages, heart rate and blood
pressure drop, metabolic rate and glucose consumption fall, and muscles
relax. In normal sleep architecture, NREM sleep makes up about 75% of
total sleep time; stage 1 accounting for 5-10% of total sleep time, stage
2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%. About
90 minutes after sleep onset, NREM sleep gives way to the first REM sleep
episode of the night. REM makes up approximately 25% of total sleep time.
In contrast to NREM sleep, REM sleep is characterized by high pulse,
respiration, and blood pressure, as well as other physiological patterns
similar to those seen in the active waking stage. Hence, REM sleep is
also known as "paradoxical sleep." Sleep onset occurs during NREM sleep
and takes 10-20 minutes in healthy young adults. The four stages of NREM
sleep together with a REM phase form one complete sleep cycle that is
repeated throughout the duration of sleep, usually four or five times.
The cyclical nature of sleep is regular and reliable; a REM period occurs
about every 90 minutes during the night. However, the first REM period
tends to be the shortest, often lasting less than 10 minutes, whereas the
later REM periods may last up to 40 minutes. With aging, the time between
retiring and sleep onset increases and the total amount of night-time
sleep decreases because of changes in sleep architecture that impair
sleep maintenance as well as sleep quality. Both NREM (particularly
stages 3 and 4) and REM sleep are reduced. However, stage 1 NREM sleep,
which is the lightest sleep, increases with age.

[0299] As used herein, the term "delta power" means a measure of the
duration of EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and
is thought to be a measure of deeper, more refreshing sleep. Delta power
is hypothesized to be a measure of a theoretical process called Process S
and is thought to be inversely related to the amount of sleep an
individual experiences during a given sleep period. Sleep is controlled
by homeostatic mechanisms; therefore, the less one sleeps the greater the
drive to sleep. It is believed that Process S builds throughout the wake
period and is discharged most efficiently during delta power sleep. Delta
power is a measure of the magnitude of Process S prior to the sleep
period. The longer one stays awake, the greater Process S or drive to
sleep and thus the greater the delta power during NREM sleep. However,
individuals with sleep disorders have difficulty achieving and
maintaining delta wave sleep, and thus have a large build-up of Process S
with limited ability to discharge this buildup during sleep. 5-HT2A
agonists tested preclinically and clinically mimic the effect of sleep
deprivation on delta power, suggesting that subjects with sleep disorders
treated with a 5-HT2A inverse agonist or antagonist will be able to
achieve deeper more refreshing sleep. These same effects have not been
observed with currently marketed pharmacotherapies. In addition,
currently marketed pharmacotherapies for sleep have side effects such as
hangover effects or addiction that are associated with the GABA receptor.
5-HT2A inverse agonists do not target the GABA receptor and so these
side effects are not a concern.

Subjective and Objective Determinations of Sleep Disorders:

[0300] There are a number of ways to determine whether the onset, duration
or quality of sleep (e.g. non-restorative or restorative sleep) is
impaired or improved. One method is a subjective determination of the
patient, e.g., do they feel drowsy or rested upon waking. Other methods
involve the observation of the patient by another during sleep, e.g., how
long it takes the patient to fall asleep, how many times does the patient
wake up during the night, how restless is the patient during sleep, etc.
Another method is to objectively measure the stages of sleep using
polysomnography.

[0301] Polysomnography is the monitoring of multiple electrophysiological
parameters during sleep and generally includes measurement of EEG
activity, electroculographic activity and electromyographic activity, as
well as other measurements. These results, along with observations, can
measure not only sleep latency (the amount of time required to fall
asleep), but also sleep continuity (overall balance of sleep and
wakefulness) and sleep consolidation (percent of sleeping time spent in
delta-wave or restorative sleep) which may be an indication of the
quality of sleep.

[0302] There are five distinct sleep stages, which can be measured by
polysomnography: rapid eye movement (REM) sleep and four stages of
non-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4). Stage 1 NREM
sleep is a transition from wakefulness to sleep and occupies about 5% of
time spent asleep in healthy adults. Stage 2 NREM sleep, which is
characterized by specific EEG waveforms (sleep spindles and K complexes),
occupies about 50% of time spent asleep. Stages 3 and 4 NREM sleep (also
known collectively as slow-wave sleep and delta-wave sleep) are the
deepest levels of sleep and occupy about 10-20% of sleep time. REM sleep,
during which the majority of vivid dreams occur, occupies about 20-25% of
total sleep.

[0303] These sleep stages have a characteristic temporal organization
across the night. NREM stages 3 and 4 tend to occur in the first
one-third to one-half of the night and increase in duration in response
to sleep deprivation. REM sleep occurs cyclically through the night.
Alternating with NREM sleep about every 80-100 minutes. REM sleep periods
increase in duration toward the morning. Human sleep also varies
characteristically across the life span. After relative stability with
large amounts of slow-wave sleep in childhood and early adolescence,
sleep continuity and depth deteriorate across the adult age range. This
deterioration is reflected by increased wakefulness and stage 1 sleep and
decreased stages 3 and 4 sleep.

[0304] In addition, the compounds of the invention can be useful for the
treatment of the sleep disorders characterized by excessive daytime
sleepiness such as narcolepsy. Inverse agonists at the serotonin
5-HT2A receptor improve the quality of sleep at nighttime which can
decrease excessive daytime sleepiness.

[0305] Accordingly, another aspect of the present invention relates to the
therapeutic use of compounds of the present invention for the treatment
of Sleep Disorders. Compounds of the present invention are potent inverse
agonists at the serotonin 5-HT2A receptor and can be effective in
the treatment of Sleep Disorders by promoting one or more of the
following: reducing the sleep onset latency period (measure of sleep
induction), reducing the number of nighttime awakenings, and prolonging
the amount of time in delta-wave sleep (measure of sleep quality
enhancement and sleep consolidation) without effecting REM sleep. In
addition, compounds of the present invention can be effective either as a
monotherapy or in combination with sleep inducing agents, for example but
not limited to, antihistamines.

[0306] 6. Diabetic-Related Pathologies:

[0307] Although hyperglycemia is the major cause for the pathogenesis of
diabetic complications such as diabetic peripheral neuropathy (DPN),
diabetic nephropathy (DN) and diabetic retinopathy (DR), increased plasma
serotonin concentration in diabetic patients has also been implicated to
play a role in disease progression (Pietraszek, M. H., et al. Thrombosis
Res. 1992, 66(6), 765-74; and Andrzejewska-Buczko J, et al., Klin Oczna.
1996; 98(2), 101-4). Serotonin is believed to play a role in vasospasm
and increased platelet aggregability. Improving microvascular blood flow
is able to benefit diabetic complications.

[0308] A recent study by Cameron and Cotter in Naunyn Schmiedebergs Arch
Pharmacol. 2003 June; 367(6):607-14, used a 5-HT2A antagonist
experimental drug AT-1015, and other non-specific 5-HT2A antagonists
including ritanserin and sarpogrelate. These studies found that all three
drugs were able to produce a marked correction (82.6-99.7%) of a 19.8%
sciatic motor conduction deficit in diabetic rats. Similarly, 44.7% and
14.9% reductions in sciatic endoneurial blood flow and saphenous sensory
conduction velocity were completely reversed.

[0309] In a separate patient study, sarpogrelate was evaluated for the
prevention of the development or progression of diabetic nephropathy
(Takahashi, T., et al., Diabetes Res Clin Pract. 2002 November;
58(2):123-9). In the trial of 24 months of treatment, sarpogrelate
significantly reduced urinary albumin excretion level.

[0313] Progressive multifocal leukoencephalopathy (PML) is a lethal
demyelinating disease caused by an opportunistic viral infection of
oligodendrocytes in immunocompromised patients. The causative agent is JC
virus, a ubiquitous papovavirus that infects the majority of the
population before adulthood and establishes a latent infection in the
kidney. In immunocompromised hosts, the virus can reactivate and
productively infect oligodendrocytes. This previously rare condition,
until 1984 reported primarily in persons with underlying
lymphoproliferative disorders, is now more common because it occurs in 4%
of patients with AIDS. Patients usually present with relentlessly
progressive focal neurologic defects, such as hemiparesis or visual field
deficits, or with alterations in mental status. On brain MRI, one or more
white matter lesions are present; they are hyperintense on T2-weighted
images and hypointense on T1-weighted images. There is no mass effect,
and contrast enhancement is rare. Diagnosis can be confirmed by brain
biopsy, with demonstration of virus by in situ hybridization or
immunocytochemistry. Polymerase chain reaction amplification of JC virus
sequences from the CSF can confirm diagnosis without the need for biopsy
[see, e.g., Antinori et al., Neurology (1997) 48:687-694; Berger and
Major, Seminars in Neurology (1999) 19:193-200; and Portegies, et al.,
Eur. J. Neurol. (2004) 11:297-304]. Currently, there is no effective
therapy. Survival after diagnosis is about 3 to 5 months in AIDS
patients.

[0315] 5-HT2A antagonists including inverse agonists have been
contemplated to be useful in the treatment of PML [Elphick et al.,
Science (2004) 306:1380-1383]. Prophylactic treatment of HIV-infected
patients with 5-HT2A antagonists is envisioned to prevent the spread
of JC virus to the central nervous system and the development of PML.
Aggressive therapeutic treatment of patients with PML is envisioned to
reduce viral spread within the central nervous system and prevent
additional episodes of demyelination.

[0316] In some embodiments, methods are provided for treating progressive
multifocal leukoencephalopathy in a patient in need of such treatment,
comprising administering to the patient a composition comprising a
5-HT2A inverse agonist disclosed herein.

[0320] 5-HT2A inverse agonists are also effective for the treatment of
pain. Sarpogrelate has been observed to provide a significant analgesic
effect both on thermal induced pain in rats after intraperitoneal
administration and on inflammatory pain in rats after either intrathecal
or intraperitoneal administration (see, Nishiyama, T. Eur. J. Pharmacol.
516:18-22 2005). This same 5-HT2A inverse agonist in humans has been
shown to be an effective treatment for lower back pain, leg pain and
numbness associated with sciatica brought on by lumbar disc herniation
(see, Kanayama, M. et al. J. Neurosurg: Spine 2:441-446 2005).

Representative Methods of the Invention:

[0321] One aspect of the present invention pertains to methods for
modulating the activity of a 5-HT2A serotonin receptor by contacting
the receptor with a compound according to any of the embodiments
described herein or a pharmaceutical composition.

[0322] One aspect of the present invention pertains to methods for the
treatment of platelet aggregation in an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound according to any of the embodiments
described herein or a pharmaceutical composition.

[0323] One aspect of the present invention pertains to methods for the
treatment of an indication selected from the group consisting of coronary
artery disease, myocardial infarction, transient ischemic attack, angina,
stroke, and atrial fibrillation in an individual comprising administering
to the individual in need thereof a therapeutically effective amount of a
compound according to any of the embodiments described herein or a
pharmaceutical composition.

[0324] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an angioplasty or coronary
bypass surgery individual comprising administering to the individual in
need thereof a therapeutically effective amount of a compound according
to any of the embodiments described herein or a pharmaceutical
composition.

[0325] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an individual suffering from
atrial fibrillation, comprising administering to the individual in need
thereof a therapeutically effective amount of a compound according to any
of the embodiments described herein or a pharmaceutical composition.

[0326] One aspect of the present invention pertains to methods for the
treatment of asthma in an individual comprising administering to the
individual in need thereof a therapeutically effective amount of a
compound according to any of the embodiments described herein or a
pharmaceutical composition.

[0327] One aspect of the present invention pertains to methods for the
treatment of a symptom of asthma in an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound according to any of the embodiments
described herein or a pharmaceutical composition.

[0328] One aspect of the present invention pertains to methods for the
treatment of agitation or a symptom thereof in an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound according to any of the embodiments
described herein or a pharmaceutical composition. In some embodiments,
the individual is a cognitively intact elderly individual.

[0329] One aspect of the present invention pertains to methods for the
treatment of agitation or a symptom thereof in an individual suffering
from dementia comprising administering to the individual in need thereof
a therapeutically effective amount of a compound according to any of the
embodiments described herein or a pharmaceutical composition. In some
embodiments, the dementia is due to a degenerative disease of the nervous
system. In some embodiments, the dementia is Alzheimers disease, Lewy
body, Parkinson's disease or Huntington's disease. In some embodiments,
the dementia is due to diseases that affect blood vessels. In some
embodiments, the dementia is due to stroke or multi-infarct dementia.

[0330] One aspect of the present invention pertains to methods for the
treatment of an individual suffering from at least one of the indications
selected from the group consisting of behavioral disorder, drug induced
psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic
disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute
schizophrenia, chronic schizophrenia and NOS schizophrenia comprising
administering to the individual in need thereof a therapeutically
effective amount of a dopamine D2 receptor antagonist and a compound
according to any of the embodiments described herein or a pharmaceutical
composition. In some embodiments, the dopamine D2 receptor
antagonist is haloperidol.

[0331] One aspect of the present invention pertains to methods for the
treatment of an individual with infantile autism, Huntington's chorea, or
nausea and vomiting from chemotherapy or chemotherapeutic antibodies
comprising administering to the individual in need thereof a
therapeutically effective amount of a dopamine D2 receptor
antagonist and a compound according to any of the embodiments described
herein or a pharmaceutical composition. In some embodiments, the dopamine
D2 receptor antagonist is haloperidol.

[0332] One aspect of the present invention pertains to methods for the
treatment of schizophrenia in an individual comprising administering to
the individual in need thereof a therapeutically effective amount of a
dopamine D2 receptor antagonist and a compound according to any of
the embodiments described herein or a pharmaceutical composition. In some
embodiments, the dopamine D2 receptor antagonist is haloperidol.

[0333] One aspect of the present invention pertains to methods for the
treatment of alleviating negative symptoms of schizophrenia induced by
the administration of haloperidol to an individual suffering from the
schizophrenia, comprising administering to the individual in need thereof
a therapeutically effective amount of a compound according to any of the
embodiments described herein or a pharmaceutical composition. In some
embodiments, the haloperidol and the compound or pharmaceutical
composition are administered in separate dosage forms. In some
embodiments, the haloperidol and the compound or pharmaceutical
composition are administered in a single dosage form.

[0334] One aspect of the present invention pertains to methods for the
treatment of a sleep disorder in an individual comprising administering
to the individual in need thereof a therapeutically effective amount of a
compound according to any of the embodiments described herein or a
pharmaceutical composition.

[0336] In some embodiments, the sleep disorder is a parasomnia. In some
embodiments, the parasomnia is selected from the group consisting of
confusional arousals, sleepwalking and sleep terrors, rhythmic movement
disorder, sleep starts, sleep talking and nocturnal leg cramps. In some
embodiments, the sleep disorder is characterized by excessive daytime
sleepiness such as narcolepsy.

[0338] One aspect of the present invention pertains to methods for the
treatment of a diabetic-related disorder in an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound according to any of the embodiments
described herein or a pharmaceutical composition.

[0339] In some embodiments, the diabetic-related disorder is diabetic
peripheral neuropathy.

[0340] In some embodiments, the diabetic-related disorder is diabetic
nephropathy.

[0341] In some embodiments, the diabetic-related disorder is diabetic
retinopathy.

[0342] One aspect of the present invention pertains to methods for the
treatment of glaucoma or other diseases of the eye with abnormal
intraocular pressure.

[0343] One aspect of the present invention pertains to methods for the
treatment of progressive multifocal leukoencephalopathy in an individual
comprising administering to the individual in need thereof a
therapeutically effective amount of a compound according to any of the
embodiments described herein or a pharmaceutical composition.

[0344] In some embodiments, the individual in need thereof has a
lymphoproliferative disorder. In some embodiments, the
lymphoproliferative disorder is leukemia or lymphoma. In some
embodiments, the leukemia or lymphoma is chronic lymphocytic leukemia,
Hodgkin's disease, or the like.

[0345] In some embodiments, the individual in need thereof has a
myeloproliferative disorder.

[0346] In some embodiments, the individual in need thereof has
carcinomatosis.

[0347] In some embodiments, the individual in need thereof has a
granulomatous or inflammatory disease. In some embodiments, the
granulomatous or inflammatory disease is tuberculosis or sarcoidosis.

[0348] In some embodiments, the individual in need thereof is
immunocompromised. In some embodiments, the immunocompromised individual
has impaired cellular immunity. In some embodiments, the impaired
cellular immunity comprises impaired T-cell immunity.

[0349] In some embodiments, the individual in need thereof is infected
with HIV. In some embodiments, the HIV-infected individual has a CD4+cell
count of ≦200/mm3. In some embodiments, the HIV-infected
individual has AIDS. In some embodiments, the HIV-infected individual has
AIDS-related complex (ARC). In certain embodiments, ARC is defined as the
presence of two successive CD4+cell counts below 200/mm3 and at
least two of the following signs or symptoms: oral hairy leukoplakia,
recurrent oral candidiasis, weight loss of at least 2.5 kg or 10% of body
weight within last six months, multidermatomal herpes zoster, temperature
above 38.5° C. for more than 14 consecutive days or more than 15
days in a 30-day period, or diarrhea with more than three liquid stools
per day for at least 30 days [see, e.g., Yamada et al., Clin. Diagn.
Virol. (1993) 1:245-256].

[0351] In some embodiments, the individual in need thereof is undergoing
immunosuppressive therapy after organ transplantation. In some
embodiments, the organ is liver, kidney, lung, heart, or the like [see,
e.g., Singh et al., Transplantation (2000) 69:467-472].

[0352] In some embodiments, the individual in need thereof is undergoing
treatment for a rheumatic disease. In some embodiments, the rheumatic
disease is systemic lupus erythematosus or the like.

[0353] In some embodiments, the compound or the pharmaceutical composition
inhibits JC virus infection of human glial cells.

[0354] One aspect of the present invention encompasses processes for
preparing a composition comprising admixing a compound according any
embodiments described herein and a pharmaceutically acceptable carrier.

[0355] One aspect of the present invention is the use of a compound for
the production of a medicament for use in the treatment of a 5-HT2A
associated disorder.

[0356] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is platelet
aggregation.

[0357] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is selected from the
group consisting of coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, and atrial fibrillation.

[0358] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is a blood clot
formation in an angioplasty or coronary bypass surgery individual.

[0359] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is a blood clot
formation in an individual suffering from atrial fibrillation.

[0360] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is asthma.

[0361] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is a symptom of
asthma.

[0362] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is agitation or a
symptom thereof in an individual. In some embodiments the individual is a
cognitively intact elderly individual.

[0363] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is agitation or a
symptom thereof in an individual suffering from dementia. In some
embodiments the dementia is due to a degenerative disease of the nervous
system. In some embodiment the dementia is Alzheimers disease, Lewy body,
Parkinson's disease, or Huntington's disease. In some embodiments the
dementia is due to diseases that affect blood vessels. In some
embodiments the dementia is due to stroke or multi-infract dementia.

[0364] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder further comprising a dopamine D2
receptor antagonist wherein the disorder is selected from the group
consisting of a behavioral disorder, drug induced psychosis, excitative
psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or
NOS psychosis, psychotic disorder, psychosis, acute schizophrenia,
chronic schizophrenia and NOS schizophrenia. In some embodiments the
dopamine D2 receptor antagonist is haloperidol.

[0365] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder further comprising a dopamine D2
receptor antagonist wherein the disorder is infantile autism,
Huntington's chorea, or nausea and vomiting from chemotherapy or
chemotherapeutic antibodies. In some embodiments the dopamine D2
receptor antagonist is haloperidol.

[0366] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder further comprising a dopamine D2
receptor antagonist wherein the disorder is schizophrenia. In some
embodiments the dopamine D2 receptor antagonist is haloperidol.

[0367] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is a negative
symptom or symptoms of schizophrenia induced by the administration of
haloperidol.

[0368] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the haloperidol and the compound
or pharmaceutical composition are administered in separate dosage forms.

[0369] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the haloperidol and the compound
or pharmaceutical composition are administered in a single dosage form.

[0370] One embodiment of the present invention is the use of a compound
for the production of a medicament for use in the treatment of a
5-HT2A associated disorder wherein the disorder is progressive
multifocal leukoencephalopathy.

[0371] One aspect of the present invention are compounds according to any
of the embodiments described herein for use in a method of treatment of
the human or animal body by therapy.

[0372] One aspect of the present invention are compounds according to any
of the embodiments described herein for use in a method for the treatment
of a 5-HT2A associated disorder, as described herein, in the human
or animal body by therapy.

[0373] One aspect of the present invention are compounds according to any
of the embodiments described herein for use in a method for the treatment
of a sleep disorder, as described herein, in the human or animal body by
therapy.

[0374] One aspect of the present invention are compounds according to any
of the embodiments described herein for use in a method for the treatment
of platelet aggregation in the human or animal body by therapy.

[0375] One aspect of the present invention are compounds according to any
of the embodiments described herein for use in a method for the treatment
of progressive multifocal leukoencephalopathy in the human or animal body
by therapy.

Pharmaceutical Compositions

[0376] A further aspect of the present invention pertains to
pharmaceutical compositions comprising one or more compounds as described
herein and one or more pharmaceutically acceptable carriers. Some
embodiments pertain to pharmaceutical compositions comprising a compound
of the present invention and a pharmaceutically acceptable carrier.

[0377] Some embodiments of the present invention include a method of
producing a pharmaceutical composition comprising admixing at least one
compound according to any of the compound embodiments disclosed herein
and a pharmaceutically acceptable carrier.

[0378] Formulations may be prepared by any suitable method, typically by
uniformly mixing the active compound(s) with liquids or finely divided
solid carriers, or both, in the required proportions, and then, if
necessary, forming the resulting mixture into a desired shape.

[0379] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants, and disintegrants may
be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of solutions,
emulsions, aqueous or oily suspensions, and syrups. Alternatively, the
oral preparations may be in the form of dry powder that can be
reconstituted with water or another suitable liquid vehicle before use.
Additional additives such as suspending or emulsifying agents,
non-aqueous vehicles (including edible oils), preservatives, and
flavorings and colorants may be added to the liquid preparations.
Parenteral dosage forms may be prepared by dissolving the compound of the
invention in a suitable liquid vehicle and filter sterilizing the
solution before filling and sealing an appropriate vial or ampoule. These
are just a few examples of the many appropriate methods well known in the
art for preparing dosage forms.

[0380] A compound of the present invention can be formulated into
pharmaceutical compositions using techniques well known to those in the
art. Suitable pharmaceutically-acceptable carriers, outside those
mentioned herein, are known in the art; for example, see Remington, The
Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams
& Wilkins, (Editors: Gennaro, A. R., et al.).

[0381] While it is possible that, for use in the treatment, a compound of
the invention may, in an alternative use, be administered as a raw or
pure chemical, it is preferable however to present the compound or active
ingredient as a pharmaceutical formulation or composition further
comprising a pharmaceutically acceptable carrier.

[0382] The invention thus further provides pharmaceutical formulations
comprising a compound of the invention or a pharmaceutically acceptable
salt or derivative thereof together with one or more pharmaceutically
acceptable carriers thereof and/or prophylactic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not overly deleterious to the
recipient thereof.

[0383] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal or
parenteral (including intramuscular, sub-cutaneous and intravenous)
administration or in a form suitable for administration by inhalation,
insufflation or by a transdermal patch. Transdermal patches dispense a
drug at a controlled rate by presenting the drug for absorption in an
efficient manner with a minimum of degradation of the drug. Typically,
transdermal patches comprise an impermeable backing layer, a single
pressure sensitive adhesive and a removable protective layer with a
release liner. One of ordinary skill in the art will understand and
appreciate the techniques appropriate for manufacturing a desired
efficacious transdermal patch based upon the needs of the artisan.

[0384] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical formulations and unit dosages thereof; and in such form
may be employed as solids, such as tablets or filled capsules, or liquids
such as solutions, suspensions, emulsions, elixirs, gels or capsules
filled with the same, all for oral use, in the form of suppositories for
rectal administration; or in the form of sterile injectable solutions for
parenteral (including subcutaneous) use. Such pharmaceutical compositions
and unit dosage forms thereof may comprise conventional ingredients in
conventional proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable effective
amount of the active ingredient commensurate with the intended daily
dosage range to be employed.

[0385] For oral administration, the pharmaceutical composition may be in
the form of, for example, a tablet, capsule, suspension or liquid. The
pharmaceutical composition is preferably made in the form of a dosage
unit containing a particular amount of the active ingredient. Examples of
such dosage units are capsules, tablets, powders, granules or a
suspension, with conventional additives such as lactose, mannitol, corn
starch or potato starch; with binders such as crystalline cellulose,
cellulose derivatives, acacia, corn starch or gelatins; with
disintegrators such as corn starch, potato starch or sodium
carboxymethyl-cellulose; and with lubricants such as talc or magnesium
stearate. The active ingredient may also be administered by injection as
a composition wherein, for example, saline, dextrose or water may be used
as a suitable pharmaceutically acceptable carrier.

[0386] Compounds of the present invention or a solvate or physiologically
functional derivative thereof can be used as active ingredients in
pharmaceutical compositions, specifically as 5-HT2A receptor
modulators. By the term "active ingredient" is defined in the context of
a "pharmaceutical composition" and shall mean a component of a
pharmaceutical composition that provides the primary pharmacological
effect, as opposed to an "inactive ingredient" which would generally be
recognized as providing no pharmaceutical benefit.

[0387] The dose when using the compounds of the present invention can vary
within wide limits, as is customary and is known to the physician, it is
to be tailored to the individual conditions in each individual case. It
depends, for example, on the nature and severity of the illness to be
treated, on the condition of the patient, on the compound employed or on
whether an acute or chronic disease state is treated or prophylaxis is
conducted or on whether further active compounds are administered in
addition to the compounds of the present invention. Representative doses
of the present invention include, but are not limited to, about 0.001 mg
to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to
about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about
0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to
about 25 mg. Multiple doses may be administered during the day,
especially when relatively large amounts are deemed to be needed, for
example 2, 3 or 4, doses. Depending on the individual and as deemed
appropriate from the patient's physician or care-giver it may be
necessary to deviate upward or downward from the doses described herein.

[0388] The amount of active ingredient, or an active salt or derivative
thereof, required for use in treatment will vary not only with the
particular salt selected but also with the route of administration, the
nature of the condition being treated and the age and condition of the
patient and will ultimately be at the discretion of the attendant
physician or clinician. In general, one skilled in the art understands
how to extrapolate in vivo data obtained in a model system, typically an
animal model, to another, such as a human. In some circumstances, these
extrapolations may merely be based on the weight of the animal model in
comparison to another, such as a mammal, preferably a human, however,
more often, these extrapolations are not simply based on weights, but
rather incorporate a variety of factors. Representative factors include
the type, age, weight, sex, diet and medical condition of the patient,
the severity of the disease, the route of administration, pharmacological
considerations such as the activity, efficacy, pharmacokinetic and
toxicology profiles of the particular compound employed, whether a drug
delivery system is utilized, or whether an acute or chronic disease state
is being treated or prophylaxis is conducted or on whether further active
compounds are administered in addition to the compounds of the present
invention and as part of a drug combination. The dosage regimen for
treating a disease condition with the compounds and/or compositions of
this invention is selected in accordance with a variety factors as cited
above. Thus, the actual dosage regimen employed may vary widely and
therefore may deviate from a preferred dosage regimen and one skilled in
the art will recognize that dosage and dosage regimen outside these
typical ranges can be tested and, where appropriate, may be used in the
methods of this invention.

[0389] The desired dose may conveniently be presented in a single dose or
as divided doses administered at appropriate intervals, for example, as
two, three, four or more sub-doses per day. The sub-dose itself may be
further divided, e.g., into a number of discrete loosely spaced
administrations. The daily dose can be divided, especially when
relatively large amounts are administered as deemed appropriate, into
several, for example 2, 3 or 4, part administrations. If appropriate,
depending on individual behavior, it may be necessary to deviate upward
or downward from the daily dose indicated.

[0390] The compounds of the present invention can be administrated in a
wide variety of oral and parenteral dosage forms. It will be obvious to
those skilled in the art that the following dosage forms may comprise, as
the active component, either a compound of the invention or a
pharmaceutically acceptable salt of a compound of the invention.

[0391] For preparing pharmaceutical compositions from the compounds of the
present invention, the selection of a suitable pharmaceutically
acceptable carrier can be either solid, liquid or a mixture of both.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier can be
one or more substances which may also act as diluents, flavouring agents,
solubilizers, lubricants, suspending agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.

[0392] In powders, the carrier is a finely divided solid which is in a
mixture with the finely divided active component.

[0393] In tablets, the active component is mixed with the carrier having
the necessary binding capacity in suitable proportions and compacted to
the desire shape and size.

[0394] The powders and tablets may contain varying percentage amounts of
the active compound. A representative amount in a powder or tablet may
contain from 0.5 to about 90 percent of the active compound; however, an
artisan would know when amounts outside of this range are necessary.
Suitable carriers for powders and tablets are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a
low melting wax, cocoa butter, and the like. The term "preparation" is
intended to include the formulation of the active compound with
encapsulating material as carrier providing a capsule in which the active
component, with or without carriers, is surrounded by a carrier, which is
thus in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.

[0395] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted and
the active component is dispersed homogeneously therein, as by stirring.
The molten homogenous mixture is then poured into convenient sized molds,
allowed to cool, and thereby to solidify.

[0396] Formulations suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams or sprays containing
in addition to the active ingredient such carriers as are known in the
art to be appropriate.

[0397] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions. For
example, parenteral injection liquid preparations can be formulated as
solutions in aqueous polyethylene glycol solution. Injectable
preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a nontoxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.

[0398] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for example
bolus injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The pharmaceutical
compositions may take such forms as suspensions, solutions, or emulsions
in oily or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Alternatively, the
active ingredient may be in powder form, obtained by aseptic isolation of
sterile solid or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0399] Aqueous formulations suitable for oral use can be prepared by
dissolving or suspending the active component in water and adding
suitable colorants, flavours, stabilizing and thickening agents, as
desired.

[0400] Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material, such
as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, or other well known suspending agents.

[0401] Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for oral
administration. Such liquid forms include solutions, suspensions, and
emulsions. These preparations may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and
natural sweeteners, dispersants, thickeners, solubilizing agents, and the
like.

[0402] For topical administration to the epidermis the compounds according
to the invention may be formulated as ointments, creams or lotions, or as
a transdermal patch.

[0403] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening and/or
gelling agents. Lotions may be formulated with an aqueous or oily base
and will in general also contain one or more emulsifying agents,
stabilizing agents, dispersing agents, suspending agents, thickening
agents, or coloring agents.

[0404] Formulations suitable for topical administration in the mouth
include lozenges comprising active agent in a flavored base, usually
sucrose and acacia or tragacanth; pastilles comprising the active
ingredient in an inert base such as gelatin and glycerin or sucrose and
acacia; and mouthwashes comprising the active ingredient in a suitable
liquid carrier.

[0405] Solutions or suspensions are applied directly to the nasal cavity
by conventional means, for example with a dropper, pipette or spray. The
formulations may be provided in single or multi-dose form. In the latter
case of a dropper or pipette, this may be achieved by the patient
administering an appropriate, predetermined volume of the solution or
suspension. In the case of a spray, this may be achieved for example by
means of a metering atomizing spray pump.

[0406] Administration to the respiratory tract may also be achieved by
means of an aerosol formulation in which the active ingredient is
provided in a pressurized pack with a suitable propellant. If the
compounds of the present invention or pharmaceutical compositions
comprising them are administered as aerosols, for example as nasal
aerosols or by inhalation, this can be carried out, for example, using a
spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered
inhaler or a dry powder inhaler. Pharmaceutical forms for administration
of the compounds of the present invention as an aerosol can be prepared
by processes well-known to the person skilled in the art. For their
preparation, for example, solutions or dispersions of the compounds of
the present invention in water, water/alcohol mixtures or suitable saline
solutions can be employed using customary additives, for example benzyl
alcohol or other suitable preservatives, absorption enhancers for
increasing the bioavailability, solubilizers, dispersants and others,
and, if appropriate, customary propellants, for example include carbon
dioxide, CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane,
or dichlorotetrafluoroethane; and the like. The aerosol may conveniently
also contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.

[0407] In formulations intended for administration to the respiratory
tract, including intranasal formulations, the compound will generally
have a small particle size for example of the order of 10 microns or
less. Such a particle size may be obtained by means known in the art, for
example by micronization. When desired, formulations adapted to give
sustained release of the active ingredient may be employed.

[0408] Alternatively the active ingredients may be provided in the form of
a dry powder, for example, a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The
powder composition may be presented in unit dose form for example in
capsules or cartridges of, e.g., gelatin, or blister packs from which the
powder may be administered by means of an inhaler.

[0409] The pharmaceutical preparations are preferably in unit dosage
forms. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets, capsules,
and powders in vials or ampoules. Also, the unit dosage form can be a
capsule, tablet, cachet, or lozenge itself, or it can be the appropriate
number of any of these in packaged form.

[0410] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.

[0412] The acid addition salts may be obtained as the direct products of
compound synthesis. In the alternative, the free base may be dissolved in
a suitable solvent containing the appropriate acid, and the salt isolated
by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of this invention may form solvates with standard low
molecular weight solvents using methods known to the skilled artisan.

[0413] Some embodiments of the present invention include a method of
producing a pharmaceutical composition for "combination-therapy"
comprising admixing at least one compound according to any of the
compound embodiments disclosed herein, together with at least one known
pharmaceutical agent as described herein and a pharmaceutically
acceptable carrier.

[0414] It is noted that when the 5-HT2A receptor modulators are
utilized as active ingredients in a pharmaceutical composition, these are
not intended for use only in humans, but in other non-human mammals as
well. Indeed, recent advances in the area of animal health-care mandate
that consideration be given for the use of active agents, such as
5-HT2A receptor modulators, for the treatment of a 5-HT2A
mediated disease or disorder in domestic animals (e.g., cats and dogs)
and in other domestic animals (e.g., such as cows, chickens, fish, etc.).
Those of ordinary skill in the art are readily credited with
understanding the utility of such compounds in such settings.

Combination Therapy:

[0415] While the compounds of the present invention can be administered as
the sole active pharmaceutical agent (i.e., mono-therapy), they can also
be used in combination with other pharmaceutical agents (i.e.,
combination-therapy) for the treatment of the
diseases/conditions/disorders described herein. Accordingly, another
aspect of the present invention includes methods of treatment of
5-HT2A serotonin receptor associated disorders diseases comprising
administering to an individual in need of such treatment a
therapeutically-effective amount of a compound of the present invention
in combination with one or more additional pharmaceutical agent as
described herein.

[0416] Suitable pharmaceutical agents that can be used in combination with
the compounds of the present invention include other antiplatelet,
antithrombotic or anticoagulant drugs, anti-arrhythmic agents,
Cholesteryl ester transfer protein (CETP) inhibitors, Niacin or niacin
analogs, Adenosine or adenosine analogs, Nitroglycerin or nitrates,
prothrombolytic agents, and the like. Other pharmaceutical agents,
including the agents set forth infra, are well known or will be readily
apparent in light of the instant disclosure, to one of ordinary skill in
the art.

[0418] The compound of the present invention can also be used in
combination with anti-arrhythmic agents such as for atrial fibrillation,
for example, amiodarone or dofetilide.

[0419] The compound of the present invention can also be used in
combination with Cholesteryl ester transfer protein (CETP) inhibitors for
dislipidemia and atherosclerosis, Niacin or niacin analogs for
dislipidemia and atherosclerosis, Adenosine or adenosine analogs for
vasodilation, Nitroglycerin or nitrates for vasodilation.

[0420] The compounds of the present invention can be used in combination
with prothrombolytic agents, such as tissue plasminogen activator
(natural or recombinant), streptokinase, reteplase, activase,
lanoteplase, urokinase, prourokinase, anisolated streptokinase
plasminogen activator complex (ASPAC), animal salivary gland plasminogen
activators, and the like. The compounds of the present invention may also
be used in combination with β-adrenergic agonists such as albuterol,
terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or
fenoterol; anticholinergics such as ipratropium bromide;
anti-inflammatory cortiocosteroids such as beclomethasone,
triarricinolone, budesonide, fluticasone, flunisolide or dexamethasone;
and anti-inflammatory agents such as cromolyn, nedocromil, theophylline,
zileuton, zafirlukast, monteleukast and pranleukast.

[0422] In a certain embodiment, a compound of the invention can be used in
conjunction with highly active antiretroviral therapy (HAART). When
antiretroviral drugs are used in combinations of three or four drugs,
this treatment is called HAART [see, e.g., Portegies, et al., Eur. J.
Neurol. (2004) 11:297-304].

[0423] In accordance with the present invention, the combination of a
compound of the present invention and pharmaceutical agent can be
prepared by mixing the respective active components either all together
or independently with a pharmaceutically acceptable carrier, excipient,
binder, diluent, etc. as described herein, and administering the mixture
or mixtures either orally or non-orally as a pharmaceutical
composition(s). When a compound or a mixture of compounds of Formula (Ia)
are administered as a combination therapy with another active compound
each can be formulated as separate pharmaceutical compositions given at
the same time or at different times. Alternatively, in some embodiments,
pharmaceutical compositions of the present invention comprise a compound
or a mixture of compounds of Formula (Ia) and the pharmaceutical agent(s)
as a single pharmaceutical composition.

Other Utilities

[0424] Another object of the present invention relates to radio-labeled
compounds of the present invention that would be useful not only in
radio-imaging but also in assays, both in vitro and in vivo, for
localizing and quantitating the 5-HT2A receptor in tissue samples,
including human, and for identifying 5-HT2A receptor ligands by
inhibition binding of a radio-labeled compound. It is a further object of
this invention to develop novel 5-HT2A receptor assays of which
comprise such radio-labeled compounds.

[0425] The present invention embraces isotopically-labeled compounds of
the present invention. An "isotopically" or "radio-labeled" compounds are
those which are identical to compounds disclosed herein, but for the fact
that one or more atoms are replaced or substituted by an atom having an
atomic mass or mass number different from the atomic mass or mass number
typically found in nature (i.e., naturally occurring). Suitable
radionuclides that may be incorporated in compounds of the present
invention include, but are not limited to, 2H (also written as D for
deuterium), 3H (also written as T for tritium), 11C, 13C,
14C, 13N, 15N, 15O, 17O, 18O, 18F,
35S, 36Cl, 82Br, 75Br, 76Br, 77Br,
123I, 124I, 125I and 131I. The radionuclide that is
incorporated in the instant radio-labeled compounds will depend on the
specific application of that radio-labeled compound. For example, for in
vitro 5-HT2A receptor labeling and competition assays, compounds
that incorporate 3H, 14C, 82Br, 125I, 131I,
35S or will generally be most useful. For radio-imaging applications
11C, 18F, 125I, 123I, 124I, 131I,
75Br, 76Br or 77Br will generally be most useful.

[0426] It is understood that a "radio-labeled" or "labeled compound" is a
compound of Formula (Ia) that has incorporated at least one radionuclide;
in some embodiments the radionuclide is selected from the group
consisting of 3H, 14C, 125I, 35S and 82Br.
Certain isotopically-labeled compounds of the present invention are
useful in compound and/or substrate tissue distribution assays. In some
embodiments the radionuclide 3H and/or 14C isotopes are useful
in these studies. Further, substitution with heavier isotopes such as
deuterium (i.e., 2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be preferred in
some circumstances. Isotopically labeled compounds of the present
invention can generally be prepared by following procedures analogous to
those disclosed in the Schemes supra and Examples infra, by substituting
an isotopically labeled reagent for a non-isotopically labeled reagent.
Other synthetic methods that are useful are discussed infra. Moreover, it
should be understood that all of the atoms represented in the compounds
of the invention can be either the most commonly occurring isotope of
such atoms or the more scarce radio-isotope or nonradio-active isotope.

[0427] Synthetic methods for incorporating radio-isotopes into organic
compounds are applicable to compounds of the invention and are well known
in the art. These synthetic methods, for example, incorporating activity
levels of tritium into target molecules, are as follows:

[0432] E. N-Methylation using Methyl Iodide [3H]--This procedure is
usually employed to prepare O-methyl or N-methyl (3H) products by
treating appropriate precursors with high specific activity methyl iodide
(3H). This method in general allows for higher specific activity,
such as for example, about 70-90 Ci/mmol.

[0434] A. Sandmeyer and like reactions--This procedure transforms an aryl
or heteroaryl amine into a diazonium salt, such as a tetrafluoroborate
salt, and subsequently to 125I labeled compound using Na125I. A
represented procedure was reported by Zhu, D.-G. and co-workers in J.
Org. Chem. 2002, 67, 943-948.

[0435] B. Ortho 125Iodination of phenols--This procedure allows for
the incorporation of 125I at the ortho position of a phenol as
reported by Collier, T. L. and co-workers in J. Labeled Compd Radiopharm.
1999, 42, S264-8266.

[0436] C. Aryl and heteroaryl bromide exchange with 125I--This method
is generally a two step process. The first step is the conversion of the
aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate
using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or
through an aryl or heteroaryl lithium, in the presence of a
tri-alkyltinhalide or hexaalkylditin [e.g.,
(CH3)3SnSn(CH3)3]. A represented procedure was
reported by Bas, M.-D. and co-workers in J. Labeled Compd Radiopharm.
2001, 44, S280-S282.

[0437] A radio-labeled 5-HT2A receptor compound of Formula (Ia) can
be used in a screening assay to identify/evaluate compounds. In general
terms, a newly synthesized or identified compound (i.e., test compound)
can be evaluated for its ability to reduce binding of the "radio-labeled
compound of Formula (Ia)" to the 5-HT2A receptor. Accordingly, the
ability of a test compound to compete with the "radio-labeled compound of
Formula (Ia)" for the binding to the 5-HT2A receptor directly
correlates to its binding affinity.

[0438] The labeled compounds of the present invention bind to the
5-HT2A receptor. In one embodiment the labeled compound has an
IC50 less than about 500 μM, in another embodiment the labeled
compound has an IC50 less than about 100 μM, in yet another
embodiment the labeled compound has an IC50 less than about 100
μM, in yet another embodiment the labeled compound has an IC50
less than about 1 μM, and in still yet another embodiment the labeled
inhibitor has an IC50 less than about 0.1 μM.

[0439] Other uses of the disclosed receptors and methods will become
apparent to those in the art based upon, inter alia, a review of this
disclosure.

[0440] As will be recognized, the steps of the methods of the present
invention need not be performed any particular number of times or in any
particular sequence. Additional objects, advantages, and novel features
of this invention will become apparent to those skilled in the art upon
examination of the following examples thereof, which are intended to be
illustrative and not intended to be limiting.

EXAMPLES

Example 1

Syntheses of Compounds of the Present Invention

[0441] Illustrated syntheses for compounds of the present invention are
shown in FIGS. 1 through 8 where the symbols have the same definitions as
used throughout this disclosure.

[0442] The compounds of the invention and their synthesis are further
illustrated by the following examples. The following examples are
provided to further define the invention without, however, limiting the
invention to the particulars of these examples. The compounds described
herein, supra and infra, are named according to CS Chem Draw Ultra
Version 7.0.1 or AutoNom 2000. In certain instances common names are used
and it is understood that these common names would be recognized by those
skilled in the art.

[0443] Chemistry: Proton nuclear magnetic resonance (1H NMR) spectra
were recorded on a Varian Mercury Vx-400 equipped with a 4 nucleus auto
switchable probe and z-gradient or a Bruker Avance-400 or 500 MHz
equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse)
and z-gradient. Chemical shifts are given in parts per million (ppm) with
the residual solvent signal used as reference. NMR abbreviations are used
as follows: s=singlet, d=doublet, dd=doublet of doublet, ddd=doublet of
doublet of doublet, dt=doublet of triplet, t=triplet, q=quartet,
m=multiplet, br=broad. Microwave irradiations were carried out using the
Emrys Synthesizer (Personal Chemistry). Thin-layer chromatography (TLC)
was performed on silica gel 60 F254 (Merck), preparatory thin-layer
chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm
plates (Whatman), and column chromatography was carried out on a silica
gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was
done under reduced pressure on a Buchi rotary evaporator. Celite 545®
was used during palladium filtrations.

[0453] A mixture of 2-(methylsulfonyl)ethyl methanesulfonate (16.6 mg,
81.9 μmol) and
N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzami-
de (30 mg, 81.9 μmol) in DMF was heated to 150° C. for 1 hour
under microwave irradiation in a heavy-walled sealed tube. The crude
product was purified by HPLC. The proper fractions were collected and
lyophilized to afford the title compound as a yellow solid in 18.5%
yield. LCMS m/z (%)=473 (M+H, 100).

[0509] To a solution of
N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamid-
e (61.0 mg, 0.146 mmol) and 5-amino-1H-tetrazole monohydrate (42.5 mg,
0.500 mmol) in DMA (4 mL) was added NaH (30 mg, 60% dispersion in mineral
oil) and the reaction was stirred for two hours. The resulting material
was purified by HPLC. The product was dried under reduced pressure to
afford the title compound as a white solid (12.5 mg, 20%). LCMS m/z
(%)=423 (M+H, 100).

[0510] To a solution of
N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamid-
e (62.3 mg, 0.149 mmol) and 3-amino-1H-1,2,4-triazole (38.8 mg, 0.461
mmol) in DMA (4 mL) was added NaH (58.8 mg, 60% dispersion in mineral
oil) and the reaction was stirred for two hours. The resulting material
was purified by HPLC. The product was dried under reduced pressure to
afford the title compound as a white solid (30.2 mg, 48%). LCMS m/z
(%)=422 (M+H, 100).

[0532] Acetyl chloride (388 μl, 5.44 mmol) was added dropwise to a
solution of
N-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)pheny-
l)-3-(trifluoromethyl)benzamide (270 mg, 0.544 mmol) in methanol (5.0 mL).
Zinc dust (356 mg, 5.44 mmol) was added, and the mixture was stirred at
23° C. After 1 hour, the mixture was filtered and the filtrate was
evaporated to dryness. The residue was taken up in ammonium hydroxide
(35%), diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine, dried with sodium sulfate, filtered, and
evaporated to dryness to afford the title compound as a colorless foam
which was used without further purification. LCMS m/z (%) 469.4 (M+H,
37Cl 46.9), 467.2 (M+H, 35Cl 86.1), 452.2 (51.6%), 450.1
(100.0%).

[0537] Although a variety of expression vectors are available to those in
the art, it is preferred that the vector utilized be pCMV. This vector
was deposited with the American Type Culture Collection (ATCC) on Oct.
13, 1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA) under the
provisions of the Budapest Treaty for the International Recognition of
the Deposit of Microorganisms for the Purpose of Patent Procedure. The
DNA was tested by the ATCC and determined to be viable. The ATCC has
assigned the following deposit number to pCMV: ATCC #203351.

[0538] B. Transfection Procedure

[0539] For the IP accumulation assay (Example 3), HEK293 cells were
transfected while for the DOI binding assay (Example 4) COS7 cells were
transfected. Several protocols well known in the art can be used to
transfect cells. The following protocol is representative of the
transfection procedures used herein for COS7 or 293 cells.

[0540] On day one, COS-7 cells were plated onto 24 well plates, usually
1×105 cells/well or 2×105 cells/well, respectively.
On day two, the cells were transfected by first mixing 0.25 μg cDNA in
50 μL serum-free DMEM/well and then 2 μL lipofectamine in 50 μL
serum-free DMEM/well. The solutions ("transfection media") were gently
mixed and incubated for 15-30 minutes at room temperature. The cells were
washed with 0.5 mL PBS and then 400 μL of serum free media was mixed
with the transfection media and added to the cells. The cells were then
incubated for 3-4 hours at 37° C./5% CO2. Then the
transfection media was removed and replaced with 1 mL/well of regular
growth media.

[0541] For 293 cells, on day one, 13×106 293 cells per 150 mm
plate were plated out. On day two, 2 mL of serum OptimemI (Invitrogen
Corporation) was added per plate followed by addition of 60 μL of
lipofectamine and 16 μg of cDNA. Note that lipofectamine must be added
to the OptimemI and mixed well before addition of cDNA. While complexes
between lipofectamine and the cDNA are forming, media was carefully
aspirated and cells were gently rinsed with 5 mL of OptimemI media
followed by careful aspiration. Then 12 mL of OptimemI was added to each
plate and 2 mL of transfection solution was added followed by a 5 hour
incubation at 37° C. in a 5% CO2 incubator. Plates were then
carefully aspirated and 25 mL of Complete Media were added to each plate
and cells were then incubated until used.

Example 3

Inositol Phosphate (IP) Accumulation Assays

[0542] A. 5-HT2A Receptor

[0543] Compounds of the invention are tested for their ability to activate
a 5-HT2A receptor clone using an IP accumulation assay. Briefly,
HEK293 cells are transiently transfected with a pCMV expression vector
containing a human 5-HT2A receptor (for the sequence of the receptor
see U.S. Pat. No. 6,541,209, SEQ ID NO:24) as described in Example 2. An
IP accumulation assay is performed as described below.

[0544] B. Constitutively Active 5-HT2A Receptor

[0545] Compounds of the invention are tested for their ability to inhibit
a constitutively active 5-HT2A receptor clone using an iv
accumulation assay. Briefly, 293 cells are transiently transfected with a
pCMV expression vector containing a constitutively active human
5-HT2A receptor (for the sequence of the receptor see U.S. Pat. No.
6,541,209, SEQ ID NO:30) as described in Example 2. The constitutively
active human 5-HT2A receptor contained the human 5-HT2A
receptor described in part A except that intracellular loop 3 (IC3) and
the cytoplamic tail are replaced by the corresponding human INI 5-HT2C
cDNA. An IP accumulation assay is performed as described below.

[0546] C. IP Accumulation Assay Protocol

[0547] On the day after transfections, media is removed and the cells are
washed with 5 mL PBS followed by careful aspiration. Cells are then
trypsinized with 2 mL of 0.05% trypsin for 20-30 seconds followed by
addition of 10 mL of warmed media, gently triturated to dissociate cells,
and an additional 13 mL of warmed media is gently added. Cells are then
counted and 55,000 cells are added to 96-well sterile poly-D-lysine
treated plates. Cells are allowed to attach over a six hour incubation at
37° C. in a 5% CO2 incubator. Media is then carefully
aspirated and 100 μL of warm inositol-free media plus 0.5 μCi
3H-inositol is added to each well and the plates are incubated for
18-20 hours at 37° C. in a 5% CO2 incubator.

[0548] On the next day, media is carefully aspirated and then 0.1 mL of
assay medium is added containing inositol-free/serum free media, 10 μM
pargyline, 10 mM lithium chloride, and test compound at indicated
concentrations. The plates are then incubated for three hours at
37° C. and then wells are carefully aspirated. Then 200 μL of
ice-cold 0.1M formic acid is added to each well. Plates can then be
frozen at this point at -80° C. until further processed. Frozen
plates are then thawed over the course of one hour, and the contents of
the wells (approximately 220 μL) are placed over 400 μL of washed
ion-exchange resin (AG 1-X8) contained in a Multi Screen Filtration plate
and incubated for 10 minutes followed by filtration under vacuum
pressure. Resin is then washed nine times with 200 μL of water and
then tritiated inositol phosphates (IP, IP2, and IP3) are eluted into a
collecting plate by the addition of 200 μl of 1M ammonium formate and
an additional 10 minute incubation. The eluant is then transferred to 20
mL scintillation vials, 8 mL of SuperMix or Hi-Safe scintillation
cocktails is added, and vials are counted for 0.5-1 minutes in a Wallac
1414 scintilation counter.

Example 4

Binding Assays

[0549] Compounds of the invention were tested for their ability to bind to
a 5-HT2A receptor clone membrane preparation using a radioligand
binding assay. Briefly, COS cells were transiently transfected with a
pCMV expression vector containing a human 5-HT2A receptor (for the
sequence of the receptor see U.S. Pat. No. 6,541,209, SEQ ID NO:24) as
described in Example 2.

[0551] COS7 cells transfected with recombinant human 5-HT2A receptors
were cultured for 48 hr post transfection, collected, washed with
ice-cold phosphate buffered saline, pH7.4 (PBS), and then centrifuged at
48,000×g for 20 mM at 4° C. The cell pellet was then
resuspended in wash buffer containing 20 mM HEPES pH 7.4 and 0.1 mM EDTA,
homogenized on ice using a Brinkman polytron, and recentrifuged at
48,000×g for 20 min. at 4° C. The resultant pellet was then
resuspended in 20 mM HEPES, pH 7.4, homogenized on ice, and centrifuged
(48,000×g for 20 min at 4° C.). Crude membrane pellets were
stored at -80° C. until used for radioligand binding assays.

[0552] B. [125I]DOI Radioligand Binding Assay

[0553] Radioligand binding assays for human 5-HT2A receptor was
conducted using the 5-HT2 agonist [125I]DOI as radioligand. To
define nonspecific binding, 10 μM DOI was used for all assays. For
competitive binding studies, 0.5 nM [125I]DOI was used and compounds
were assayed over a range of 0.01 nM to 10 μM. Assays were conducted
in a total volume of 200 μl in 96-well Perkin Elmer GF/C filter plates
in assay buffer (50 mM Tris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl2,
and 10 μM pargyline). Assay incubations were performed for 60 mM at
room temperature and were terminated by rapid filtration under vacuum
pressure of the reaction mixture over Whatman GF/C glass fiber filters
presoaked in 0.5% PEI using a Brandell cell harvester. Filters were then
washing several times with ice-cold wash buffer (50 mM Tris-HCl, pH 7.4).
Plates were then dried at room temperature and counted in a Wallac
microBeta scintillation counter. Certain compounds of the present
invention and their corresponding activity values are shown in the
following table.

Certain other compounds of the invention had activity values ranging from
about 10 μM to about 0.10 nM in this assay.

Example 5

In Vitro Human Platelet Aggregation Assays

[0554] Compounds of the invention were tested for their ability to
aggregate human platelets. Aggregation assays were performed using a
Chrono-Log Optical aggregometer model 410. Human blood (˜100 mL)
was collected from human donors into glass Vacutainers containing 3.8%
sodium citrate (light blue tops) at room temperature. Platelet rich
plasma (PRP) was isolated via centrifugation at 100 g for 15 min at room
temperature. After removal of the aqueous PRP layer, the platelet poor
plasma (PPP) was prepared via high speed centrifugation at 2400 g for 20
min. Platelets were counted and their concentration was set to 250,000
cells/μl by dilution with PPP. Aggregation assays were conducted
according to the manufacturer's specifications. Briefly, a suspension of
450 μl PRP was stirred in a glass cuvette (1200 rpm) and, after
baseline was established, 1 μM ADP followed by either saline or 1
μM 5HT and compound of interest (at desired concentrations) were added
and the aggregation response recorded. The concentration of ADP used
causes approximately 10-20% of maximal aggregation. The 5-HT
concentration corresponded to the concentration which produced maximal
potentiation. Percent inhibition of aggregation was calculated from the
maximum decrease in optical density of the controls and of the samples
containing inhibitors. Only the synergistic effect was assessed. Certain
compounds of the invention had activity values ranging from about 10
μM to about 5 nM in this assay.

Example 6

Efficacy of Compounds of the Invention in the Attenuation of DOI-Induced
Hypolocomotion in Rats

[0555] In this example, compounds of the invention can be tested for
inverse agonist activity by determining whether these compounds could
attenuate DOI-induced hypolocomotion in rats in a novel environment. DOI
is a potent 5-HT2A/2C receptor agonist that crosses the blood-brain
barrier. The standard protocol used is described briefly below.

Animals:

[0556] Male Sprague-Dawley rats weighing between 200-300 g are used for
all tests. Rats are housed three to four per cage. These rats are naive
to experimental testing and drug treatment. Rats are handled one to three
days before testing to acclimate them to experimental manipulation. Rats
are fasted overnight prior to testing.

Compounds:

[0557] (R)-DOI HCl (C11H16INO2HCl) can be obtained from
Sigma-Aldrich, and is dissolved in 0.9% saline. Compounds of the
invention are dissolved in 100% PEG400. DOI is injected s.c. in a volume
of 1 mL/kg, while compounds of the invention are administered p.o. in a
volume of 2 mL/kg.

Procedure:

[0558] The "Motor Monitor" (Hamilton-Kinder, Poway, Calif.) is used for
all activity measurement. This apparatus recorded rears using infrared
photobeams.

[0559] Locomotor activity testing is conducted during the light cycle
(0630-1830) between 9:00 a.m. and 4:00 p.m. Animals are allowed 30 min
acclimation to the testing room before testing began.

[0560] In determining the effects of compounds of the invention on
DOI-induced hypoactivity, animals are first injected with vehicle or the
compound of the invention (50 μmol/kg) in their home cages. Sixty
minutes later, saline or DOI (0.3 mg/kg salt) is injected. 10 min after
DOI administration, animals are placed into the activity apparatus and
rearing activity is measured for 10 minutes.

Statistics and Results:

[0561] Results (total rears over 10 minutes) are analyzed by t-test.
P<0.05 is considered significant.

Example 7

In Vitro Binding of 5-HT2A Receptor

Animals:

[0562] Animals (Sprague-Dawley rats) are sacrificed and brains are rapidly
dissected and frozen in isopentane maintained at -42° C.
Horizontal sections are prepared on a cryostat and maintained at
-20° C.

LSD Displacement Protocol:

[0563] Lysergic acid diethylamide (LSD) is a potent 5-HT2A receptor
and dopamine D2 receptor ligand. An indication of the selectivity of
compounds for either or both of these receptors involves displacement of
radiolabeled-bound LSD from pre-treated brain sections. For these
studies, radiolabeled 125I-LSD (NEN Life Sciences, Boston, Mass.,
Catalogue number NEX-199) can be utilized; spiperone (RBI, Natick, Mass.
Catalogue number s-128) a 5-HT2A receptor and dopamine D2
receptor antagonist, can also utilized. Buffer consists of 50 nanomolar
TRIS-HCl, pH 7.4.

[0565] After drying, sections are apposed to x-ray film (Kodak Hyperfilm)
and exposed for 4 days.

Example 8

Serotonin 5-HT2A Receptor Occupancy Studies in Monkey

[0566] In this example, the 5-HT2A receptor occupancy of a compound
of the invention can be measured. The study can be carried out in rhesus
monkeys using PET and 18F-altanserin.

Radioligand:

[0567] The PET radioligand used for the occupancy studies is
18F-altanserin. Radiosynthesis of 18F-altanserin is achieved in
high specific activities and is suitable for radiolabeling 5-HT2A
receptors in vivo (see Staley et al., Nucl. Med. Biol., 28:271-279 (2001)
and references cited within). Quality control issues (chemical and
radiochemical purity, specific activity, stability etc) and appropriate
binding of the radioligand are verified in rat brain slices prior to use
in PET experiments.

Drug Doses and Formulations:

[0568] Briefly, the radiopharmaceutical is dissolved in sterile 0.9%
saline, pH approx 6-7. The compounds of the invention are dissolved in
60% PEG 400-40% sterile saline on the same day of the PET experiment.

[0569] Serotonin 5-HT2A occupancy studies in humans have been
reported for M100,907 (Grunder et al., Neuropsychopharmacology,
17:175-185 (1997), and Talvik-Lofti et al., Psychopharmacology,
148:400-403 (2000)). High occupancies of the 5-HT2A receptors have
been reported for various oral doses (doses studied ranged from 6 to 20
mg). For example, an occupancy of >90% was reported for a dose of 20
mg (Talvik-Lofti et al., supra), which translates to approx. 0.28 mg/kg.
It may therefore be anticipated that an i.v. dose of 0.1 to 0.2 mg/kg of
M100,907 is likely to provide high receptor occupancy. A 0.5 mg/kg dose
of a Compound of the invention can be used in these studies.

PET Experiments:

[0570] The monkey is anesthetized by using ketamine (10 mg/kg) and is
maintained using 0.7 to 1.25% isoflurane. Typically, the monkey has two
i.v. lines, one on each arm. One i.v. line is used to administer the
radioligand, while the other line is used to draw blood samples for
pharmacokinetic data of the radioligand as well as the cold drugs.
Generally, rapid blood samples are taken as the radioligand is
administered which then taper out by the end of the scan. A volume of
approximately 1 mL of blood is taken per time point, which is spun down,
and a portion of the plasma is counted for radioactivity in the blood.

[0571] An initial control study is carried out in order to measure
baseline receptor densities. PET scans on the monkey are separated by at
least two weeks. Unlabeled Compound of the invention is administered
intravenously, dissolved in 80% PEG 400:40% sterile saline.

PET Data Analysis:

[0572] PET data are analyzed by using cerebellum as the reference region
and using the distribution volume region (DVR) method. This method has
been applied for the analysis of 18F-altanserin PET data in nonhuman
primate and human studies (Smith et al., Synapse, 30:380-392 (1998).

Example 9

The Effect of Compounds of the Invention and Zolpidem on Delta Power in
Rats

[0573] In this example, the effect of Compounds of the invention on sleep
and wakefullness can be compared to the reference drug zolpidem. Drugs
are administered during the middle of the light period (inactivity
period).

[0574] Briefly, Compounds of the invention are tested for their effects on
sleep parameters and are compared to zolpidem (5.0 mg/kg, Sigma, St.
Louis, Mo.) and vehicle control (80% Tween 80, Sigma, St. Louis, Mo.). A
repeated measures design is employed in which each rat is to receive
seven separate dosings via oral gavage. The first and seventh dosings are
vehicle and the second through sixth are the test compounds and zolpidem
given in counter-balanced order. Since all dosings are administered while
the rats are connected to the recording apparatus, 60% CO2/40%
O2 gas is employed for light sedation during the oral gavage
process. Rats are fully recovered within 60 seconds following the
procedure. A minimum of three days elapses between dosings. In order to
test the effect of the compounds on sleep consolidation, dosing occurs
during the middle of the rats' normal inactive period (6 hours following
lights on). Dosing typically occurs between 13:15 and 13:45 using a 24
hour notation. All dosing solutions are made fresh on the day of dosing.
Following each dosing, animals are continuously recorded until lights out
the following day (˜30 hours).

Animal Recording and Surgical Procedures:

[0575] Animals are housed in a temperature controlled recording room under
a 12/12 light/dark cycle (lights on at 7:00 am) and have food and water
available ad libitum. Room temperature (24±2° C.), humidity
50±20% relative humidity) and lighting conditions are monitored
continuously via computer. Drugs are administered via oral gavage as
described above, with a minimum of three days between closings. Animals
are inspected daily in accordance with NIH guidelines.

[0576] Eight male Wistar rats (300+25 g; Charles River, Wilmington, Mass.)
are prepared with chronic recording implants for continuous
electroencephalograph (EEG) and electromyograph (EMG) recordings. Under
isoflurane anesthesia (1-4%), the fur is shaved from the top of the skull
and the skin was disinfected with Betadine and alcohol. A dorsal midline
incision is made, the temporalis muscle retracted, and the skull
cauterized and thoroughly cleaned with a 2% hydrogen peroxide solution.
Stainless steel screws (#000) are implanted into the skull and served as
epidural electrodes. EEG electrodes are positioned bilaterally at +2.0 mm
AP from bregma and 2.0 mm ML and at -6.0 mm AP and 3.0 mm ML.
Multi-stranded twisted stainless steel wire electrodes are sutured
bilaterally in the neck muscles for recording of the EMG. EMG and EEG
electrodes are soldered to a head plug connector that was affixed to the
skull with dental acrylic. Incisions are closed with suture (silk 4-0)
and antibiotics administered topically. Pain is relieved by a
long-lasting analgesic (Buprenorphine) administered intramuscularly once
post-operatively. Post-surgery, each animal is placed in a clean cage and
observed until it is recovered. Animals are permitted a minimum of week
post-operative recovery before study.

[0577] For sleep recordings, animals are connected via a cable and a
counter-balanced commutator to a Neurodata model 15 data collection
system (Grass-Telefactor, West Warwick, R.I.). The animals are allowed an
acclimation period of at least 48 hours before the start of the
experiment and are connected to the recording apparatus continuously
throughout the experimental period except to replace damaged cables. The
amplified EEG and EMG signals are digitized and stored on a computer
using SleepSign software (Kissei Comtec, Irvine Calif.).

Data Analysis:

[0578] EEG and EMG data are scored visually in 10 second epochs for waking
(W), REMS, NREMS. Scored data are analyzed and expressed as time spent in
each state per half hour. Sleep bout length and number of bouts for each
state are calculated in hourly bins. A "bout" consists of a minimum of
two consecutive epochs of a given state. EEG delta power (0.5-3.5 Hz)
within NREMS is also analyzed in hourly bins. The EEG spectra during
NREMS are obtained offline with a fast Fourier transform algorithm on all
epochs without artifact. The delta power is normalized to the average
delta power in NREMS between 23:00 and 1:00, a time when delta power is
normally lowest.

[0579] Data are analyzed using repeated measures ANOVA. Light phase and
dark phase data are analyzed separately. Both the treatment effect within
each rat and the time by treatment effect within each rat is analyzed.
Since two comparisons are made, a minimum value of P<0.025 is required
for post hoc analysis. When statistical significance is found from the
ANOVAs, t-tests are performed comparing all compounds to vehicle and the
test compounds to zolpidem.

Example 10

Efficacy of Compounds of the Invention in the Inhibition of JC Virus
Infection of Human Glial Cells

[0580] A compound of the invention can be shown to inhibit JC virus
infection of human glial cells using the in vitro model of Elphick et al.
[Science (2004) 306:1380-1383], essentially as described briefly here.

[0583] The Mad-1/SVEΔ strain of JC virus [Vacante et al., Virology
(1989) 170:353-361] is used for these experiments. While the host range
of JC virus is typically limited to growth in human fetal glial cells,
the host range of Mad-1/SVEΔ extends to human kidney and monkey
cell types. Mad-1/SVEΔ is propagated in HEK cells. Virus titer is
measured by hemagglutination of human type O erythrocytes.

[0584] Assay for Inhibition of JC Virus Infection

[0585] SVG cells growing on coverslips are pre-incubated at 37° C.
for 45 min with or without the compound of the invention diluted in media
containing 2% FCS. By way of illustration and not limitation, the
compound of the invention is used at a concentration of about 1 nM to
about 100 μM, at a concentration of about 10 nM to about 100 μM, at
a concentration of about 1 nM to about 10 μM, or at a concentration of
about 10 nM to about 10 μM.

[0586] JC virus (Mad-1/SVEΔ) is then added at an MOI of 1.0 and the
cells are incubated for 1 hr at 37° C. in the continued presence
of the compound of the invention. The cells are then washed 3× in
PBS and fed with growth media containing the compound of the invention.
At 72 hr post-infection, V antigen positive cells are scored by indirect
immunofluorescence (see below). Controls include the addition of the
compound of the invention at 24 and 48 h post-infection. The percentage
of infected cells in untreated cultures is set at 100%.

[0587] Indirect Immunofluorescence

[0588] For indirect immunofluorescence analysis of V antigen expression,
SVG cells growing on coverslips are fixed in ice cold acetone. To detect
V antigen expression, the cells are then incubated for 30 min at
37° C. with a 1:10 dilution of hybridoma supernatant from PAB597.
The PAB597 hybridoma produces a monoclonal antibody against the SV40
capsid protein VP1 which has been shown to cross-react with JC virus VP1.
The cells are then washed and incubated with goat anti-mouse Alexa Fluor
488 secondary antibody for an additional 30 min. After a final wash, the
cells are counterstained with 0.05% Evan's blue, mounted onto glass
slides using 90% glycerol in PBS and visualized on Nikon E800
epifluorescent scope. Images are captured using a Hamamatsu digital
camera and analyzed using Improvision software.

Example 11

In Vitro Dog Platelet Aggregation Assays

[0589] Approximately 50 mL of blood is pooled from 3 male beagles. The
protocol for analyzing the effects of compounds on platelet aggregation
are identical to those used for human platelets (see Example 5, supra)
except 5 μM ADP and 2 μM 5-HT were used to stimulate amplification
of platelet aggregation.

Example 12

Ex-Vivo Dog Whole Blood Aggregation

[0590] One hour following PO dosing with a test compound whole blood was
collected from male beagle dogs in a 5 mL vacutainer with exogenous
heparin (5 U/mL) added to vacutainer. Aggregation studies were evaluated
by using whole blood Aggregometer (Chronolog Corp.). Briefly, whole blood
(400 uL) was added to saline (600 uL) with constant stirring and
activated with 5 ug of Collagen (Chronolog Corp.). The serotonin response
was obtained by adding 5-HT (Sigma) to final concentration of 2.5 μM.
Results: Selected compounds were tested for anti-platelet aggregation
activity after single bolus oral dosing. The dose that afforded maximal
inhibition of 5-HT amplified platelet aggregation was identified and used
for comparison.

Example 13

Rat In Vivo Thrombosis, Bleeding, Aggregation, PK Assay

Thrombosis Formation and Bleeding Time:

[0591] This model concomitantly measures thrombus formation, bleeding
time, platelet aggregation and drug exposure in a single live dosed rat.
Test compounds are administered to male rats (weighing 250-350 g) via PO
injection at varying concentrations depending on compound potency ranging
from 1 mpk-100 mpk. Animals are then anesthetized using Nembutal
approximately 30 min post PO. Once the animal is fully anesthetized using
approved surgical techniques the animal's right femoral artery is
isolated in 2 different sections approximately 4-6 mm in length, one area
for probe placement and one for Ferric Chloride patch positioning. The
artery is then allowed to stabilize to allow recovery from the surgery.
During stabilization the animal is then intubated and placed on a
ventilator (Harvard Apparatus, Inc.) at 75 strokes/min with a volume of
2.5 cubic cm. Following intubation and after stabilization a micro
arterial probe (Transonic Systems, Inc) is then placed on the distal
isolated femoral artery. Once the probe is in place the flow is monitored
using a Powerlab recording system (AD Instruments) to monitor rate of
pulsatile flow. A small piece of filter paper soaked in 30% ferric
chloride is placed on the area of the artery upstream of the probe for 10
min. After 5 min of Ferric Choloride patch placement the last 3 mm of the
rat's tail is removed. The tail is then placed in a saline filled glass
vial at 37 degree and the time it took for bleeding to stop is recorded.
After the Ferric chloride patch is removed the flow is recorded until the
artery is occluded and time to occlusion is recorded.

Whole Blood Aggregation and PK:

[0592] Following measurement of bleeding and time to occlusion 5 mL of
blood is obtained for ex-vivo aggregation analysis by cardiac puncture in
heparin (5 U/mL). An additional 500 μL of blood is collected in a
separate vacutainer for PK analysis (plasma drug concentration). Ex-vivo
aggregation studies are evaluated by using whole blood Aggregometer
(Chronolog Corp.). Briefly, whole blood (400 μL) is added to saline
(600 μL) with constant stirring and activated with 2.55 μg of
Collagen (Chronolog Corp.). The serotonin response is obtained by adding
5-HT (Sigma) to final concentration of 2.5 μM. Results: Test compounds
or reference compounds with acceptable levels of binding to rat 5-HT2A
receptors are evaluated for effects of thrombus formation, bleeding and
platelet activity in a single model. This allows for the most accurate
demonstration of separation of the test compound effects on platelet
mediated thrombus formation from effects on bleeding.

[0593] Those skilled in the art will recognize that various modifications,
additions, substitutions, and variations to the illustrative examples set
forth herein can be made without departing from the spirit of the
invention and are, therefore, considered within the scope of the
invention. All documents referenced above, including, but are not limited
to, printed publications, and provisional and regular patent
applications, are incorporated herein by reference in their entirety.

Patent applications by Bradley Teegarden, San Diego, CA US

Patent applications by Dennis Chapman, San Diego, CA US

Patent applications by Honnappa Jayakumar, San Diego, CA US

Patent applications by Konrad Feichtinger, San Diego, CA US

Patent applications by Marc Decaire, San Diego, CA US

Patent applications by Peter I. Dosa, San Diego, CA US

Patent applications by Sonja Strah-Pleynet, San Diego, CA US

Patent applications by Thuy-Anh Tran, San Diego, CA US

Patent applications in class The additional ring is a hetero ring

Patent applications in all subclasses The additional ring is a hetero ring